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Sample records for control increases myeloid

  1. Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage

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    Porse, Bo T; Bryder, David; Theilgaard-Mönch, Kim

    2005-01-01

    dissociate the ability of C/EBP alpha to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow (BM) myeloid...... progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation...

  2. Splenomegaly, myeloid lineage expansion and increased osteoclastogenesis in osteogenesis imperfecta murine.

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    Matthews, Brya G; Roeder, Emilie; Wang, Xi; Aguila, Hector Leonardo; Lee, Sun-Kyeong; Grcevic, Danka; Kalajzic, Ivo

    2017-10-01

    Osteogenesis imperfecta (OI) is a disease caused by defects in type I collagen production that results in brittle bones. While the pathology is mainly caused by defects in the osteoblast lineage, there is also elevated bone resorption by osteoclasts resulting in high bone turnover in severe forms of the disease. Osteoclasts originate from hematopoietic myeloid cells, however changes in hematopoiesis have not been previously documented in OI. In this study, we evaluated hematopoietic lineage distribution and osteoclast progenitor cell frequency in bone marrow, spleen and peripheral blood of osteogenesis imperfecta murine (OIM) mice, a model of severe OI. We found splenomegaly in all ages examined, and expansion of myeloid lineage cells (CD11b + ) in bone marrow and spleen of 7-9week old male OIM animals. OIM spleens also showed an increased frequency of purified osteoclast progenitors. This phenotype is suggestive of chronic inflammation. Isolated osteoclast precursors from both spleen and bone marrow formed osteoclasts more rapidly than wild-type controls. We found that serum TNFα levels were increased in OIM, as was IL1α in OIM females. We targeted inflammation therapeutically by treating growing animals with murine TNFR2:Fc, a compound that blocks TNFα activity. Anti-TNFα treatment marginally decreased spleen mass in OIM females, but failed to reduce bone resorption, or improve bone parameters or fracture rate in OIM animals. We have demonstrated that OIM mice have changes in their hematopoietic system, and form osteoclasts more rapidly even in the absence of OI osteoblast signals, however therapy targeting TNFα did not improve disease parameters. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Myeloid derived suppressor cells (MDSCs are increased and exert immunosuppressive activity together with polymorphonuclear leukocytes (PMNs in chronic myeloid leukemia patients.

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    Cesarina Giallongo

    Full Text Available Tumor immune tolerance can derive from the recruitment of suppressor cell population, including myeloid derived suppressor cells (MDSCs, able to inhibit T cells activity. We identified a significantly expanded MDSCs population in chronic myeloid leukemia (CML patients at diagnosis that decreased to normal levels after imatinib therapy. In addition, expression of arginase 1 (Arg1 that depletes microenvironment of arginine, an essential aminoacid for T cell function, resulted in an increase in patients at diagnosis. Purified CML CD11b+CD33+CD14-HLADR- cells markedly suppressed normal donor T cell proliferation in vitro. Comparing CML Gr-MDSCs to autologous polymorphonuclear leukocytes (PMNs we observed a higher Arg1 expression and activity in PMNs, together with an inhibitory effect on T cells in vitro. Our data indicate that CML cells create an immuno-tolerant environment associated to MDSCs expansion with immunosuppressive capacity mediated by Arg1. In addition, we demonstrated for the first time also an immunosuppressive activity of CML PMNs, suggesting a strong potential immune escape mechanism created by CML cells, which control the anti-tumor reactive T cells. MDSCs should be monitored in imatinib discontinuation trials to understand their importance in relapsing patients.

  4. Circulating endothelial cells are increased in chronic myeloid leukemia blast crisis

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    C.R.T. Godoy

    2015-06-01

    Full Text Available We measured circulating endothelial precursor cells (EPCs, activated circulating endothelial cells (aCECs, and mature circulating endothelial cells (mCECs using four-color multiparametric flow cytometry in the peripheral blood of 84 chronic myeloid leukemia (CML patients and 65 healthy controls; and vascular endothelial growth factor (VEGF by quantitative real-time PCR in 50 CML patients and 32 healthy controls. Because of an increase in mCECs, the median percentage of CECs in CML blast crisis (0.0146% was significantly higher than in healthy subjects (0.0059%, P0.05. In addition, VEGF gene expression was significantly higher in all phases of CML: 0.245 in blast crisis, 0.320 in the active phase, and 0.330 in chronic phase patients than it was in healthy subjects (0.145. In conclusion, CML in blast crisis had increased levels of CECs and VEGF gene expression, which may serve as markers of disease progression and may become targets for the management of CML.

  5. Pam2 lipopeptides systemically increase myeloid-derived suppressor cells through TLR2 signaling

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    Maruyama, Akira; Shime, Hiroaki, E-mail: shime@med.hokudai.ac.jp; Takeda, Yohei; Azuma, Masahiro; Matsumoto, Misako; Seya, Tsukasa, E-mail: seya-tu@pop.med.hokudai.ac.jp

    2015-02-13

    Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exhibit potent immunosuppressive activity. They are increased in tumor-bearing hosts and contribute to tumor development. Toll-like receptors (TLRs) on MDSCs may modulate the tumor-supporting properties of MDSCs through pattern-recognition. Pam2 lipopeptides represented by Pam2CSK4 serve as a TLR2 agonist to exert anti-tumor function by dendritic cell (DC)-priming that leads to NK cell activation and cytotoxic T cell proliferation. On the other hand, TLR2 enhances tumor cell progression/invasion by activating tumor-infiltrating macrophages. How MDSCs respond to TLR2 agonists has not yet been determined. In this study, we found intravenous administration of Pam2CSK4 systemically up-regulated the frequency of MDSCs in EG7 tumor-bearing mice. The frequency of tumor-infiltrating MDSCs was accordingly increased in response to Pam2CSK4. MDSCs were not increased by Pam2CSK4 stimuli in TLR2 knockout (KO) mice. Adoptive transfer experiments using CFSE-labeled MDSCs revealed that the TLR2-positive MDSCs survived long in tumor-bearing mice in response to Pam2CSK4 treatment. Since the increased MDSC population sustained immune-suppressive properties, our study suggests that Pam2CSK4-triggered TLR2 activation enhances the MDSC potential and suppress antitumor immune response in tumor microenvironment. - Highlights: • Pam2CSK4 administration induces systemic accumulation of CD11b{sup +}Gr1{sup +} MDSCs. • TLR2 is essential for Pam2CSK4-induced accumulation of CD11b{sup +}Gr1{sup +} MDSCs. • Pam2CSK4 supports survival of CD11b{sup +}Gr1{sup +} MDSCs in vivo.

  6. Deficiency of leptin receptor in myeloid cells disrupts hypothalamic metabolic circuits and causes body weight increase

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    Yuanqing Gao

    2018-01-01

    Conclusions: Myeloid cell leptin receptor deficient mice partially replicate the db/db phenotype. Leptin signaling in hypothalamic microglia is important for microglial function and a correct formation of the hypothalamic neuronal circuit regulating metabolism.

  7. Myeloid differentiation factor 88 (MyD88-deficiency increases risk of diabetes in mice.

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    Toru Hosoi

    Full Text Available BACKGROUND: Multiple lines of evidence suggest innate immune response pathways to be involved in the development of obesity-associated diabetes although the molecular mechanism underling the disease is unknown. Recent observations suggest that saturated fatty acids can act as a ligand for toll-like receptor (TLR 4, which is thought to mediate obesity-associated insulin resistance. Myeloid differentiation factor 88 (MyD88 is an adapter protein for TLR/IL-1 receptor signaling, which is involved in the activation of inflammatory pathways. To evaluate molecular mechanisms linking obesity-associated diabetes down-stream of TLR4, we investigated physiological role of MyD88 in high-fat diet (HFD-induced obesity. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found MyD88-deficient mice fed a HFD had increased circulating levels of insulin, leptin and cholesterol, as well as liver dysfunction (increased induction of ALT levels, increased activation of JNK and cleavage of PARP, which were linked to the onset of severe diabetes. On the other hand, TNF-alpha would not be involved in HFD-induced diabetes in MyD88-deficient mice, because TNF-alpha level was attenuated in MyD88-deficient mice fed with HFD. CONCLUSIONS/SIGNIFICANCE: The present finding of an unexpected role for MyD88 in preventing diabetes may provide a potential novel target/strategy for treating metabolic syndrome.

  8. Increased granulocytic, erythrocytic, and megakaryocytic progenitors in myelofibrosis with myeloid metaplasia

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    Chikkappa, G.; Carsten, A.L.; Chanana, A.D.; Chandra, P.; Cronkite, E.P.

    1978-01-01

    Nucleated cells obtained from blood and/or bone marrow of patients with myelofibrosis with myeloid metaplasia (MMM) were cultured in diffusion chambers (DC) implanted into the peritoneal cavities of irradiated mice. A total of five blood studies and two bone marrow studies were performed using cells obtained from five patients. The DC were harvested at intervals from the host mice and the total and differential cellularity of DC contents were evaluated. The results obtained from MMM cultures were compared with those from similar cultures of blood cells and marrow cells of four and six normal individuals respectively. The proliferation and maturation of the granulocytic, erythrocytic, and megakaryocytic lines in MMM cultures occurred in an orderly fashion as they occur in vivo. The patterns of proliferation and maturation of the three cell lines in cultures after day 7 suggest that they primarily originate from progenitor cells. The numbers of granulocytes in the multiplicative pool, recognizable red cell precursors, and megakaryocytes recovered were significantly greater from the MMM cultures than those from the normal blood or marrow cultures. These results suggest that the blood and marrow cells of MMM patients have increased numbers of progenitors for granulocytes, erythrocytes and megakaryocytes

  9. Imatinib Increases Serum Creatinine by Inhibiting Its Tubular Secretion in a Reversible Fashion in Chronic Myeloid Leukemia.

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    Vidal-Petiot, Emmanuelle; Rea, Delphine; Serrano, Fidéline; Stehlé, Thomas; Gardin, Claude; Rousselot, Philippe; Peraldi, Marie-Noëlle; Flamant, Martin

    2016-03-01

    Monitoring renal function is important in imatinib-treated patients with chronic myeloid leukemia because serum creatinine may increase during the course of therapy. The mechanism of this increase and its reversibility on treatment cessation have never been investigated. We retrospectively analyzed data from imatinib-treated patients explored in our renal physiology unit with measurement of glomerular filtration rate (urinary clearance of (51)CrEDTA) and of urinary clearance and tubular secretion of creatinine. Results were compared with those of controls matched for measured glomerular filtration rate, age, gender, and ethnicity. We also analyzed variations of serum creatinine before and during imatinib cessation and after imatinib resumption in patients enrolled in imatinib discontinuation studies. In 4 imatinib-treated patients who underwent thorough renal exploration, the part of creatinine clearance due to tubular secretion was negligible (2.4, 3.1, -1.3, and 2.8 mL/min) and significantly lower than that measured in their respective controls (17.7 ± 5.6, 43.0 ± 18.0, 23.1 ± 6.7, and 18.6 ± 5.6 mL/min, P creatinine tubular secretion (20.3 vs. 17.9 ± 5.2 mL/min in the control population, P = .2). In 15 patients of imatinib discontinuation studies, a median decrease in serum creatinine of 17.9% was observed after imatinib cessation. Resumption of treatment in 6 patients led to a median increase in serum creatinine of 18.8%. Imatinib completely blunts tubular secretion of creatinine, a previously unreported pharmacologic property. This inhibition increases serum creatinine independently of any glomerular dysfunction and is fully reversible on imatinib cessation. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

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    Möllgård, Lars; Saft, Leonie; Treppendahl, Marianne Bach

    2011-01-01

    Background Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ...... hybridization for del(5q31). DESIGN AND METHODS: Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial...... the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4...

  11. ZFX Controls Propagation and Prevents Differentiation of Acute T-Lymphoblastic and Myeloid Leukemia

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    Stuart P. Weisberg

    2014-02-01

    Full Text Available Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML and acute T-lymphoblastic leukemia (T-ALL originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.

  12. The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.

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    Hucke, Stephanie; Herold, Martin; Liebmann, Marie; Freise, Nicole; Lindner, Maren; Fleck, Ann-Katrin; Zenker, Stefanie; Thiebes, Stephanie; Fernandez-Orth, Juncal; Buck, Dorothea; Luessi, Felix; Meuth, Sven G; Zipp, Frauke; Hemmer, Bernhard; Engel, Daniel Robert; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa

    2016-09-01

    Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

  13. Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

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    Möllgård, Lars; Saft, Leonie; Treppendahl, Marianne Bach

    2011-01-01

    Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization...

  14. ZRF1 controls the retinoic acid pathway and regulates leukemogenic potential in acute myeloid leukemia.

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    Demajo, S; Uribesalgo, I; Gutiérrez, A; Ballaré, C; Capdevila, S; Roth, M; Zuber, J; Martín-Caballero, J; Di Croce, L

    2014-11-27

    Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is highly overexpressed in human AML, but it is not known whether it plays a role in leukemia progression. Here, we demonstrate that ZRF1 depletion decreases cell proliferation, induces apoptosis and enhances cell differentiation in human AML cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through its interaction with the RA receptor α (RARα) and its binding to RA target genes. Our genome-wide expression study reveals that ZRF1 regulates the transcription of nearly half of RA target genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis, and differentiation, ZRF1 depletion strongly inhibits leukemia progression in a xenograft mouse model. Finally, ZRF1 knockdown cooperates with RA treatment in leukemia suppression in vivo. Taken together, our data reveal that ZRF1 is a key transcriptional regulator in leukemia progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML treatment.

  15. Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer.

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    Wesolowski, Robert; Duggan, Megan C; Stiff, Andrew; Markowitz, Joseph; Trikha, Prashant; Levine, Kala M; Schoenfield, Lynn; Abdel-Rasoul, Mahmoud; Layman, Rachel; Ramaswamy, Bhuvaneswari; Macrae, Erin R; Lustberg, Maryam B; Reinbolt, Raquel E; Mrozek, Ewa; Byrd, John C; Caligiuri, Michael A; Mace, Thomas A; Carson, William E

    2017-11-01

    This study sought to evaluate whether myeloid-derived suppressor cells (MDSC) could be affected by chemotherapy and correlate with pathologic complete response (pCR) in breast cancer patients receiving neo-adjuvant chemotherapy. Peripheral blood levels of granulocytic (G-MDSC) and monocytic (M-MDSC) MDSC were measured by flow cytometry prior to cycle 1 and 2 of doxorubicin and cyclophosphamide and 1st and last administration of paclitaxel or paclitaxel/anti-HER2 therapy. Of 24 patients, 11, 6 and 7 patients were triple negative, HER2+ and hormone receptor+, respectively. 45.8% had pCR. Mean M-MDSC% were types. G-MDSC levels at the last draw were numerically lower in patients with pCR (1.15; 95% CI 0.14-2.16) versus patients with no pCR (2.71; 95% CI 0-5.47). There was no significant rise in G-MDSC from draw 1 to 3 in African American patients, and at draw 3 G-MDSC levels were significantly lower in African Americans versus Caucasians (p < 0.05). It was concluded that G-MDSC% increased during doxorubicin and cyclophosphamide therapy, but did not significantly differ between patients based on pathologic complete response.

  16. Chemotherapy alters the increased numbers of myeloid-derived suppressor and regulatory T cells in children with acute lymphoblastic leukemia.

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    Salem, Mohamed Labib; El-Shanshory, Mohamed R; Abdou, Said H; Attia, Mohamed S; Sobhy, Shymaa M; Zidan, Mona F; Zidan, Abdel-Aziz A

    2018-04-01

    Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The precise mechanism behind the relapse in this disease is not clearly known. One possible mechanism could be the accumulation of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (T regs ) which we and others have reported to mediate suppression of anti-tumor immune responses. In this study, we aimed to analyze the numbers of these cells in a population of B-ALL pediatric patients. Peripheral blood samples withdrawn from B-ALL pediatric patients (n = 45 before, during and after the induction phase of chemotherapy. Using multi parametric flow cytometric analysis. MDSCs were identified as Lin - HLA-DR - CD33 + CD11b + ; and T reg cells were defined as CD4 + CD25 + CD127 -/low . Early diagnosed B-ALL patients showed significant increases in the numbers of MDSCs and T regs as compared to healthy volunteers. During induction of chemotherapy, however, the patients showed higher and lower numbers of MDSCs and T reg cells, respectively as compared to early diagnosed patients (i.e., before chemotherapy). After induction of chemotherapy, the numbers of MDSCs and T reg cells showed higher increases and decreases, respectively as compared to the numbers in patients during chemotherapy. Our results indicate that B-ALL patients harbor high numbers of both MDSCs and T regs cells. This pilot study opens a new avenue to investigate the mechanism mediating the emergence of these cells on larger number of B-ALL patients at different treatment stages.

  17. Association of Increased F4/80high Macrophages With Suppression of Serum-Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells.

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    Huang, Qi-Quan; Birkett, Robert; Doyle, Renee E; Haines, G Kenneth; Perlman, Harris; Shi, Bo; Homan, Philip; Xing, Lianping; Pope, Richard M

    2017-09-01

    Macrophages are critical in the pathogenesis of rheumatoid arthritis (RA). We recently demonstrated that FLIP is necessary for the differentiation and/or survival of macrophages. We also showed that FLIP is highly expressed in RA synovial macrophages. This study was undertaken to determine if a reduction in FLIP in mouse macrophages reduces synovial tissue macrophages and ameliorates serum-transfer arthritis. Mice with Flip deleted in myeloid cells (Flip f/f LysM c/+ mice) and littermate controls were used. Arthritis was induced by intraperitoneal injection of K/BxN serum. Disease severity was evaluated by clinical score and change in ankle thickness, and joints were examined by histology and immunohistochemistry. Cells were isolated from the ankles and bone marrow of the mice and examined by flow cytometry, real-time quantitative reverse transcriptase-polymerase chain reaction, or Western blotting. In contrast to expectations, Flip f/f LysM c/+ mice developed more severe arthritis early in the clinical course, but peak arthritis was attenuated and the resolution phase more complete than in control mice. Prior to the induction of serum-transfer arthritis, the number of tissue-resident macrophages was reduced. On day 9 after arthritis induction, the number of F4/80 high macrophages in the joints of the Flip f/f LysM c/+ mice was not decreased, but increased. FLIP was reduced in the F4/80 high macrophages in the ankles of the Flip f/f LysM c/+ mice, while F4/80 high macrophages expressed an antiinflammatory phenotype in both the Flip f/f LysM c/+ and control mice. Our observations suggest that reducing FLIP in macrophages by increasing the number of antiinflammatory macrophages may be an effective therapeutic approach to suppress inflammation, depending on the disease stage. © 2017, American College of Rheumatology.

  18. MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias

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    Spinello, I; Quaranta, M T; Riccioni, R; Riti, V; Pasquini, L; Boe, A; Pelosi, E [Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome (Italy); Vitale, A; Foà, R [Department of Cellular Biotechnologies and Hematology, Division of Hematology, ‘Sapienza' University, Rome (Italy); Testa, U; Labbaye, C [Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome (Italy)

    2011-06-01

    CXCR4 is a negative prognostic marker in acute myeloid leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-leukemia drugs, for development of new therapeutic strategies.

  19. MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias

    International Nuclear Information System (INIS)

    Spinello, I; Quaranta, M T; Riccioni, R; Riti, V; Pasquini, L; Boe, A; Pelosi, E; Vitale, A; Foà, R; Testa, U; Labbaye, C

    2011-01-01

    CXCR4 is a negative prognostic marker in acute myeloid leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-leukemia drugs, for development of new therapeutic strategies

  20. Control of Both Myeloid Cell Infiltration and Angiogenesis by CCR1 Promotes Liver Cancer Metastasis Development in Mice

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    Mathieu Paul Rodero

    2013-06-01

    Full Text Available Expression of the CC chemokine receptor 1 (CCR1 by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy.

  1. Naturally occurring CD4+ CD25+ FOXP3+ T-regulatory cells are increased in chronic myeloid leukemia patients not in complete cytogenetic remission and can be immunosuppressive.

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    Rojas, Jose M; Wang, Lihui; Owen, Sally; Knight, Katy; Watmough, Sarah J; Clark, Richard E

    2010-12-01

    Clinical presentation of chronic myeloid leukemia (CML) requires not only the deregulated tyrosine kinase BCR-ABL, but also the failure of an immune response against BCR-ABL-expressing cells. T-cell responses against BCR-ABL and other antigens are well-described, but their relevance to the in vivo control of CML is unclear. The suppressive role of naturally occurring T regulatory (T-reg) cells in antitumor immunity is well-established, although little is known about their role in modulating the T-cell response to BCR-ABL. Naturally occurring T-reg cells were characterized and quantified by flow cytometry in 39 CML patients and 10 healthy donors. Their function was studied by observing their effect on responses to purified protein derivative, a recall antigen, and on the response of an autologous T-cell line recognizing BCR-ABL. T-reg cells were CD4(+), CD25(+), FOXP3(+), CD127(low), and CD62L(high). T-reg numbers in patients in complete cytogenetic remission were significantly lower than in patients not in complete cytogenetic remission (p T-reg cell depletion using anti-CD25 selection enhanced proliferative responses to purified protein derivative. Furthermore, the interferon-γ and/or granzyme-B production of effector cells specific for viral peptides or a BCR-ABL HLA-A3-restricted peptide was inhibited when autologous T-reg cells were present. Taken together, these data suggest a role for T-reg cells in limiting immune responses in CML patients and this may include immune responses to BCR-ABL. The increased frequency of T-reg cells in patients with high levels of BCR-ABL transcripts indicates that an immune mechanism may be important in the control of CML. Copyright © 2010 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  2. Aberrant DNA Methylation in Chronic Myeloid Leukemia: Cell Fate Control, Prognosis, and Therapeutic Response.

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    Behzad, Masumeh Maleki; Shahrabi, Saeid; Jaseb, Kaveh; Bertacchini, Jessika; Ketabchi, Neda; Saki, Najmaldin

    2018-01-31

    Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the expression of the BCR-ABL1 fusion gene with different chimeric transcripts. Despite the crucial impact of constitutively active tyrosine kinase in CML pathogenesis, aberrant DNA methylation of certain genes plays an important role in disease progression and the development of drug resistance. This article reviews recent findings relevant to the effect of DNA methylation pattern of regulatory genes on various cellular activities such as cell proliferation and survival, as well as cell-signaling molecules in CML. These data might contribute to defining the role of aberrant DNA methylation in disease initiation and progression. However, further studies are needed on the validation of specific aberrant methylation markers regarding the prognosis and prediction of response among the CML patients.

  3. Social defeat promotes a reactive endothelium in a brain region-dependent manner with increased expression of key adhesion molecules, selectins and chemokines associated with the recruitment of myeloid cells to the brain.

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    Sawicki, C M; McKim, D B; Wohleb, E S; Jarrett, B L; Reader, B F; Norden, D M; Godbout, J P; Sheridan, J F

    2015-08-27

    Repeated social defeat (RSD) in mice causes myeloid cell trafficking to the brain that contributes to the development of prolonged anxiety-like behavior. Myeloid cell recruitment following RSD occurs in regions where neuronal and microglia activation is observed. Thus, we hypothesized that crosstalk between neurons, microglia, and endothelial cells contributes to brain myeloid cell trafficking via chemokine signaling and vascular adhesion molecules. Here we show that social defeat caused an exposure- and brain region-dependent increase in several key adhesion molecules and chemokines involved in the recruitment of myeloid cells. For example, RSD induced distinct patterns of adhesion molecule expression that may explain brain region-dependent myeloid cell trafficking. VCAM-1 and ICAM-1 mRNA expression were increased in an exposure-dependent manner. Furthermore, RSD-induced VCAM-1 and ICAM-1 protein expression were localized to the vasculature of brain regions implicated in fear and anxiety responses, which spatially corresponded to previously reported patterns of myeloid cell trafficking. Next, mRNA expression of additional adhesion molecules (E- and P-selectin, PECAM-1) and chemokines (CXCL1, CXCL2, CXCL12, CCL2) were determined in the brain. Social defeat induced an exposure-dependent increase in mRNA levels of E-selectin, CXCL1, and CXCL2 that increased with additional days of social defeat. While CXCL12 was unaffected by RSD, CCL2 expression was increased by six days of social defeat. Last, comparison between enriched CD11b(+) cells (microglia/macrophages) and enriched GLAST-1(+)/CD11b(-) cells (astrocytes) revealed RSD increased mRNA expression of IL-1β, CCL2, and CXCL2 in microglia/macrophages but not in astrocytes. Collectively, these data indicate that key mediators of leukocyte recruitment were increased in the brain vasculature following RSD in an exposure- and brain region-dependent manner. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights

  4. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-a may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission......%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-a2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-a2b arm (82%) compared...... with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-a2b treatment ( 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-a2b to imatinib markedly increased the MMR rate at 12 months...

  5. Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy.

    Science.gov (United States)

    Sandri, Sara; De Sanctis, Francesco; Lamolinara, Alessia; Boschi, Federico; Poffe, Ornella; Trovato, Rosalinda; Fiore, Alessandra; Sartori, Sara; Sbarbati, Andrea; Bondanza, Attilio; Cesaro, Simone; Krampera, Mauro; Scupoli, Maria T; Nishimura, Michael I; Iezzi, Manuela; Sartoris, Silvia; Bronte, Vincenzo; Ugel, Stefano

    2017-10-20

    Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.

  6. CD33+ HLA-DR– Myeloid-Derived Suppressor Cells Are Increased in Frequency in the Peripheral Blood of Type1 Diabetes Patients with Predominance of CD14+ Subset

    Directory of Open Access Journals (Sweden)

    Mirhane Hassan

    2018-02-01

    Full Text Available INTRODUCTION: Type 1 Diabetes Mellitus (T1D is an autoimmune disease that results from the destruction of insulin-producing beta cells of the pancreas by autoreactive T cells. Myeloid-derived suppressor cells (MDSCs are a heterogeneous population of cells that can potently suppress T cell responses. AIM: To detect the presence of MDSCs in T1D and compare their percentage in T1D versus healthy individuals. METHOD: Thirty T1D patients were included in the study. Diabetic patients with nephropathy (n = 18 and diabetic patients without nephropathy (n = 12. A control group of healthy individuals (n = 30 were also included. CD33+ and HLA-DR– markers were used to identify MDSCs by flow cytometry. CD14 positive and negative MDSCs subsets were also identified. RESULTS: MDSCs was significantly increased in T1D than the control group and diabetic patient with nephropathy compared to diabetic patients without nephropathy. M-MDSCs (CD14+ CD33+ HLA–DR− were the most abundant MDSCs subpopulation in all groups, however their percentage decrease in T1D than the control group. CONCLUSION: MDSCs are increased in the peripheral blood of T1D with a predominance of the CD14+ MDSCs subset. Future studies are needed to test the immune suppression function of MDSCs in T1D.

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

    Science.gov (United States)

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

    2016-01-01

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

  8. Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC).

    Science.gov (United States)

    Giallongo, Cesarina; Tibullo, Daniele; Parrinello, Nunziatina L; La Cava, Piera; Di Rosa, Michelino; Bramanti, Vincenzo; Di Raimondo, Cosimo; Conticello, Concetta; Chiarenza, Annalisa; Palumbo, Giuseppe A; Avola, Roberto; Romano, Alessandra; Di Raimondo, Francesco

    2016-12-27

    Granulocytic-Myeloid-derived suppressor cells (G-MDSC) are increased in Multiple Myeloma (MM) patients but the mechanisms of G-MDSC generation are still unknown. There are many evidences of the role of mesenchymal stem cells (MSC) in promoting MM cell growth, survival and drug-resistance. We here used a specific experimental model in vitro to evaluate the ability of MSC to induce G-MDSC. We found that although MSC derived from healthy donors (HD), MGUS and MM were able to generate the same amount of MDSC, only MM-MSC-educated G-MDSC exhibited suppressive ability. In addition, in comparison with MSC derived from HD, MM-MSC produce higher amount of immune-modulatory factors that could be involved in MDSC induction. Compared to G-MDSC obtained from co-culture models with MSC from healthy subjects, both MGUS and MM-MSC-educated G-MDSC showed increase of immune-modulatory factors. However, only MM-MSC educated G-MDSC 1) up-regulated immune-suppressive factors as ARG1 and TNFα, 2) expressed higher levels of PROK2, important in angiogenesis and inflammatory process, and 3) showed ability to digest bone matrix.Our data demonstrate that MM-MSC are functionally different from healthy subjects and MGUS-MSC, supporting an evolving concept regarding the contribution of MM-MSC to tumor development and progression.

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

    Science.gov (United States)

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

    2018-02-01

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

  10. Exercising self-control increases approach motivation.

    Science.gov (United States)

    Schmeichel, Brandon J; Harmon-Jones, Cindy; Harmon-Jones, Eddie

    2010-07-01

    The present research tested the hypothesis that exercising self-control causes an increase in approach motivation. Study 1 found that exercising (vs. not exercising) self-control increases self-reported approach motivation. Study 2a identified a behavior--betting on low-stakes gambles--that is correlated with approach motivation but is relatively uncorrelated with self-control, and Study 2b observed that exercising self-control temporarily increases this behavior. Last, Study 3 found that exercising self-control facilitates the perception of a reward-relevant symbol (i.e., a dollar sign) but not a reward-irrelevant symbol (i.e., a percent sign). Altogether, these results support the hypothesis that exercising self-control temporarily increases approach motivation. Failures of self-control that follow from prior efforts at self-control (i.e., ego depletion) may be explained in part by increased approach motivation.

  11. Checkpoints to the Brain: Directing Myeloid Cell Migration to the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Meredith Harrison-Brown

    2016-12-01

    Full Text Available Myeloid cells are a unique subset of leukocytes with a diverse array of functions within the central nervous system during health and disease. Advances in understanding of the unique properties of these cells have inspired interest in their use as delivery vehicles for therapeutic genes, proteins, and drugs, or as “assistants” in the clean-up of aggregated proteins and other molecules when existing drainage systems are no longer adequate. The trafficking of myeloid cells from the periphery to the central nervous system is subject to complex cellular and molecular controls with several ‘checkpoints’ from the blood to their destination in the brain parenchyma. As important components of the neurovascular unit, the functional state changes associated with lineage heterogeneity of myeloid cells are increasingly recognized as important for disease progression. In this review, we discuss some of the cellular elements associated with formation and function of the neurovascular unit, and present an update on the impact of myeloid cells on central nervous system (CNS diseases in the laboratory and the clinic. We then discuss emerging strategies for harnessing the potential of site-directed myeloid cell homing to the CNS, and identify promising avenues for future research, with particular emphasis on the importance of untangling the functional heterogeneity within existing myeloid subsets.

  12. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remissio...

  13. Cytomegalovirus immune evasion of myeloid lineage cells.

    Science.gov (United States)

    Brinkmann, Melanie M; Dağ, Franziska; Hengel, Hartmut; Messerle, Martin; Kalinke, Ulrich; Čičin-Šain, Luka

    2015-06-01

    Cytomegalovirus (CMV) evades the immune system in many different ways, allowing the virus to grow and its progeny to spread in the face of an adverse environment. Mounting evidence about the antiviral role of myeloid immune cells has prompted the research of CMV immune evasion mechanisms targeting these cells. Several cells of the myeloid lineage, such as monocytes, dendritic cells and macrophages, play a role in viral control, but are also permissive for CMV and are naturally infected by it. Therefore, CMV evasion of myeloid cells involves mechanisms that qualitatively differ from the evasion of non-CMV-permissive immune cells of the lymphoid lineage. The evasion of myeloid cells includes effects in cis, where the virus modulates the immune signaling pathways within the infected myeloid cell, and those in trans, where the virus affects somatic cells targeted by cytokines released from myeloid cells. This review presents an overview of CMV strategies to modulate and evade the antiviral activity of myeloid cells in cis and in trans.

  14. Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients.

    Science.gov (United States)

    Bryant, A; Nivison-Smith, I; Pillai, E S; Kennedy, G; Kalff, A; Ritchie, D; George, B; Hertzberg, M; Patil, S; Spencer, A; Fay, K; Cannell, P; Berkahn, L; Doocey, R; Spearing, R; Moore, J

    2014-01-01

    This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

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

    Science.gov (United States)

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

    2018-01-01

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

  16. Regulatory Myeloid Cells in Transplantation

    Science.gov (United States)

    Rosborough, Brian R.; Raïch-Regué, Dàlia; Turnquist, Heth R.; Thomson, Angus W.

    2013-01-01

    Regulatory myeloid cells (RMC) are emerging as novel targets for immunosuppressive (IS) agents and hold considerable promise as cellular therapeutic agents. Herein, we discuss the ability of regulatory macrophages (Mreg), regulatory dendritic cells (DCreg) and myeloid-derived suppressor cells (MDSC) to regulate alloimmunity, their potential as cellular therapeutic agents and the IS agents that target their function. We consider protocols for the generation of RMC and the selection of donor- or recipient-derived cells for adoptive cell therapy. Additionally, the issues of cell trafficking and antigen (Ag) specificity following RMC transfer are discussed. Improved understanding of the immunobiology of these cells has increased the possibility of moving RMC into the clinic to reduce the burden of current IS agents and promote Ag-specific tolerance. In the second half of this review, we discuss the influence of established and experimental IS agents on myeloid cell populations. IS agents believed historically to act primarily on T cell activation and proliferation are emerging as important regulators of RMC function. Better insights into the influence of IS agents on RMC will enhance our ability to develop cell therapy protocols to promote the function of these cells. Moreover, novel IS agents may be designed to target RMC in situ to promote Ag-specific immune regulation in transplantation and usher in a new era of immune modulation exploiting cells of myeloid origin. PMID:24092382

  17. Health Care Resource Utilization and Costs in Patients with Chronic Myeloid Leukemia with Better Adherence to Tyrosine Kinase Inhibitors and Increased Molecular Monitoring Frequency.

    Science.gov (United States)

    Latremouille-Viau, Dominick; Guerin, Annie; Gagnon-Sanschagrin, Patrick; Dea, Katherine; Cohen, Benjamin G; Joseph, George J

    2017-02-01

    Frequent molecular monitoring (qPCR tests), as recommended by evidence-based monitoring guidelines, is associated with higher adherence to tyrosine kinase inhibitors (TKIs) in the management of chronic myeloid leukemia (CML); both factors have been associated with better clinical and economic outcomes. To (a) estimate the effect of more frequent qPCR tests on health care resource utilization (HRU) and associated costs, including direct (effect of qPCR test frequency on HRU) and indirect (through TKI adherence) effects, and (b) develop an economic model applicable to multiple clinical practice scenarios. Adult patients newly diagnosed with CML who started TKI firstline therapy were identified from U.S. administrative claims data (2010-2015). TKI adherence (medication possession ratio [MPR]), number of inpatient days, emergency room (ER) visits, outpatient service days, and mean costs per HRU event were measured during the first year of CML treatment. Direct and indirect effects of qPCR test frequency were estimated using multivariate regression models. Subsequently, an economic model was developed to assess the overall effect of varying qPCR test frequency on HRU and associated costs during the first year of CML treatment under different clinical practice scenarios; the scenario reported is the increase from 1 to 2 qPCR tests. Of the 1,431 patients included, 36% had no qPCR tests, the average qPCR test frequency was 1.6, and the average MPR was 0.86 during the first year of CML treatment. The direct effect of increasing qPCR test frequency by 1 was associated with 13.0% fewer inpatient days (adjusted incidence rate ratio [adjusted IRR] = 0.87; P = 0.010); 8.3% fewer ER visits (adjusted IRR = 0.92; P = 0.043); and 3.0% more outpatient service days (adjusted IRR = 1.03; P = 0.002). Each increase of 1 test was associated with an increase in TKI adherence by 2.2 percentage points (adjusted MPR difference = 0.022; P better adherence to TKIs were associated with lower HRU

  18. Dual effect of LPS on murine myeloid leukemia cells: Pro-proliferation and anti-proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Lingling [Department of Pediatrics, Jingjiang People' s Hospital, Yangzhou University, Jingjiang 214500 (China); Noncoding RNA Center, Yangzhou University, Yangzhou 225001 (China); Zhao, Yingmin [Department of Pediatrics, Jingjiang People' s Hospital, Yangzhou University, Jingjiang 214500 (China); Gu, Xin; Wang, Jijun; Pang, Lei; Zhang, Yanqing; Li, Yaoyao; Jia, Xiaoqin; Wang, Xin [Noncoding RNA Center, Yangzhou University, Yangzhou 225001 (China); Gu, Jian [Department of Hematology, Yangzhou University School of Clinical Medicine, Yangzhou 225001 (China); Yu, Duonan, E-mail: duonan@yahoo.com [Department of Pediatrics, Jingjiang People' s Hospital, Yangzhou University, Jingjiang 214500 (China); Noncoding RNA Center, Yangzhou University, Yangzhou 225001 (China); Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Disease, Yangzhou 225001 (China); Institute of Comparative Medicine, Yangzhou University, Yangzhou 225001 (China); Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou 225001 (China)

    2016-06-10

    Modification of the bone marrow microenvironment is considered as a promising strategy to control leukemic cell proliferation, diseases progression and relapse after treatment. However, due to the diversity and complexity of the cellular and molecular compartments in the leukemic microenvironment, it is extremely difficult to dissect the role of each individual molecule or cell type in vivo. Here we established an in vitro system to dissect the role of lipopolysaccharide (LPS), stromal cells and endothelial cells in the growth of mouse myeloid tumor cells and B-lymphoma cells. We found that either LPS or bone marrow stromal cells as a feeder layer in culture is required for the proliferation of myeloid tumor cells. Surprisingly, the growth of myeloid leukemic cells on stromal cells is strongly inhibited when coupled with LPS in culture. This opposing effect of LPS, a complete switch from pro-proliferation to antitumor growth is due, at least in part, to the rapidly increased production of interleukin 12, Fas ligand and tissue inhibitor of metalloproteinases-2 from stromal cells stimulated by LPS. These results demonstrate that LPS can either facilitate or attenuate tumor cell proliferation, thus changing the disease course of myeloid leukemias through its direct effect or modulation of the tumor microenvironment. - Highlights: • LPS alone in culture is required for the proliferation of murine myeloid tumor cells. • Bone marrow stromal cells as a feeder layer is also required for the proliferation of myeloid tumor cells. • However, the growth of myeloid tumor cells is inhibited when LPS and stromal cells are both available in culture. • Thus LPS can either facilitate or attenuate tumor growth through its direct effect or modulation of tumor microenvironment.

  19. Dual effect of LPS on murine myeloid leukemia cells: Pro-proliferation and anti-proliferation

    International Nuclear Information System (INIS)

    Yu, Lingling; Zhao, Yingmin; Gu, Xin; Wang, Jijun; Pang, Lei; Zhang, Yanqing; Li, Yaoyao; Jia, Xiaoqin; Wang, Xin; Gu, Jian; Yu, Duonan

    2016-01-01

    Modification of the bone marrow microenvironment is considered as a promising strategy to control leukemic cell proliferation, diseases progression and relapse after treatment. However, due to the diversity and complexity of the cellular and molecular compartments in the leukemic microenvironment, it is extremely difficult to dissect the role of each individual molecule or cell type in vivo. Here we established an in vitro system to dissect the role of lipopolysaccharide (LPS), stromal cells and endothelial cells in the growth of mouse myeloid tumor cells and B-lymphoma cells. We found that either LPS or bone marrow stromal cells as a feeder layer in culture is required for the proliferation of myeloid tumor cells. Surprisingly, the growth of myeloid leukemic cells on stromal cells is strongly inhibited when coupled with LPS in culture. This opposing effect of LPS, a complete switch from pro-proliferation to antitumor growth is due, at least in part, to the rapidly increased production of interleukin 12, Fas ligand and tissue inhibitor of metalloproteinases-2 from stromal cells stimulated by LPS. These results demonstrate that LPS can either facilitate or attenuate tumor cell proliferation, thus changing the disease course of myeloid leukemias through its direct effect or modulation of the tumor microenvironment. - Highlights: • LPS alone in culture is required for the proliferation of murine myeloid tumor cells. • Bone marrow stromal cells as a feeder layer is also required for the proliferation of myeloid tumor cells. • However, the growth of myeloid tumor cells is inhibited when LPS and stromal cells are both available in culture. • Thus LPS can either facilitate or attenuate tumor growth through its direct effect or modulation of tumor microenvironment.

  20. Testicular myeloid sarcoma: case report.

    Science.gov (United States)

    Zago, Luzia Beatriz Ribeiro; Ladeia, Antônio Alexandre Lisbôa; Etchebehere, Renata Margarida; de Oliveira, Leonardo Rodrigues

    2013-01-01

    Myeloid sarcomas are extramedullary solid tumors composed of immature granulocytic precursor cells. In association with acute myeloid leukemia and other myeloproliferative disorders, they may arise concurrently with compromised bone marrow related to acute myeloid leukemia, as a relapsed presentation, or occur as the first manifestation. The testicles are considered to be an uncommon site for myeloid sarcomas. No therapeutic strategy has been defined as best but may include chemotherapy, radiotherapy and/or hematopoietic stem cell transplantation. This study reports the evolution of a patient with testicular myeloid sarcoma as the first manifestation of acute myeloid leukemia. The patient initially refused medical treatment and died five months after the clinical condition started.

  1. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.

    Science.gov (United States)

    Ravandi, Farhad; Ritchie, Ellen K; Sayar, Hamid; Lancet, Jeffrey E; Craig, Michael D; Vey, Norbert; Strickland, Stephen A; Schiller, Gary J; Jabbour, Elias; Erba, Harry P; Pigneux, Arnaud; Horst, Heinz-August; Recher, Christian; Klimek, Virginia M; Cortes, Jorge; Roboz, Gail J; Odenike, Olatoyosi; Thomas, Xavier; Havelange, Violaine; Maertens, Johan; Derigs, Hans-Günter; Heuser, Michael; Damon, Lloyd; Powell, Bayard L; Gaidano, Gianluca; Carella, Angelo-Michele; Wei, Andrew; Hogge, Donna; Craig, Adam R; Fox, Judith A; Ward, Renee; Smith, Jennifer A; Acton, Gary; Mehta, Cyrus; Stuart, Robert K; Kantarjian, Hagop M

    2015-09-01

    Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355

  2. The plant cytoskeleton controls regulatory volume increase.

    Science.gov (United States)

    Liu, Qiong; Qiao, Fei; Ismail, Ahmed; Chang, Xiaoli; Nick, Peter

    2013-09-01

    The ability to adjust cell volume is required for the adaptation to osmotic stress. Plant protoplasts can swell within seconds in response to hypoosmotic shock suggesting that membrane material is released from internal stores. Since the stability of plant membranes depends on submembraneous actin, we asked, whether this regulatory volume control depends on the cytoskeleton. As system we used two cell lines from grapevine which differ in their osmotic tolerance and observed that the cytoskeleton responded differently in these two cell lines. To quantify the ability for regulatory volume control, we used hydraulic conductivity (Lp) as readout and demonstrated a role of the cytoskeleton in protoplast swelling. Chelation of calcium, inhibition of calcium channels, or manipulation of membrane fluidity, did not significantly alter Lp, whereas direct manipulation of the cytoskeleton via specific chemical reagents, or indirectly, through the bacterial elicitor Harpin or activation of phospholipase D, was effective. By optochemical engineering of actin using a caged form of the phytohormone auxin we can break the symmetry of actin organisation resulting in a localised deformation of cell shape indicative of a locally increased Lp. We interpret our findings in terms of a model, where the submembraneous cytoskeleton controls the release of intracellular membrane stores during regulatory volume change. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Acute myeloid leukemia (AML) - children

    Science.gov (United States)

    Acute myeloid leukemia is a cancer of the blood and bone marrow. Bone marrow is the soft tissue inside ... develops quickly. Both adults and children can get acute myeloid leukemia ( AML ). This article is about AML in children.

  4. Hepatic ischemia and reperfusion injury in the absence of myeloid cell-derived COX-2 in mice.

    Directory of Open Access Journals (Sweden)

    Sergio Duarte

    Full Text Available Cyclooxygenase-2 (COX-2 is a mediator of hepatic ischemia and reperfusion injury (IRI. While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9 expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.

  5. THERAPY-RELATED MYELOID MALIGNANCIES IN MYELOMA

    Directory of Open Access Journals (Sweden)

    Xenofon Papanikolaou

    2011-10-01

    Full Text Available Therapy related myeloid malignancies are an increasingly recognized treatment complication in patients undergoing therapy for multiple myeloma. The main predisposing factors are the alkylating agents, topoisomerase II inhibitors and radiotherapy, but recently questions have been raised regarding the immunomodulatory agent lenalidomide. Little is known about the new antimyeloma agents in the context of therapy related myeloid malignanices. The duration of treatment and the time from diagnosis are the main contributing factors in alkylating induced myeloid malignancies which occur 5-10 years after treatment, chromosome 5 and 7 abnormalities being the characteristic finding. High dose therapy (HDT does not seem to be a major contributing factor per se in multiple myeloma. In a number of large published series, all the factors related with therapy-induced myelodysplasia were defined prior to HDT. Topoisomerase II inhibitors induce mainly acute leukemias which invariably correlate with dysregulation of the MLL gene. Radiotherapy causes therapy related myelodysplasia if applied in bone marrow producing areas, especially if combined with chemotherapy. Therapy related myeloid malignancies generally herald a poor prognosis. Karyotypic abnormalities seem to be the main prognostic factor. In all cases the risk for therapy related myeloid malignancies drops sharply by 10 years after the treatment.

  6. THERAPY-RELATED MYELOID MALIGNANCIES IN MYELOMA

    Directory of Open Access Journals (Sweden)

    Bart Barlogie

    2011-01-01

    Full Text Available

    Therapy related myeloid malignancies are an increasingly recognized treatment complication in patients undergoing therapy for multiple myeloma. The main predisposing factors are the alkylating agents, topoisomerase II inhibitors and radiotherapy, but recently questions have been raised regarding the immunomodulatory agent lenalidomide. Little is known about the new antimyeloma agents in the context of therapy related myeloid malignanices. The duration of treatment and the time from diagnosis are the main contributing factors in alkylating induced myeloid malignancies which occur 5-10 years after treatment, chromosome 5 and 7 abnormalities being the characteristic finding. High dose therapy (HDT does not seem to be a major contributing factor per se in multiple myeloma. In a number of large published series, all the factors related with therapy-induced myelodysplasia were defined prior to HDT. Topoisomerase II inhibitors induce mainly acute leukemias which invariably correlate with dysregulation of the MLL gene. Radiotherapy causes therapy related myelodysplasia if applied in bone marrow producing areas, especially if combined with chemotherapy. Therapy related myeloid malignancies generally herald a poor prognosis. Karyotypic abnormalities seem to be the main prognostic factor. In all cases the risk for therapy related myeloid malignancies drops sharply by 10 years after the treatment.

  7. Omega 3 fatty acids reduce myeloid progenitor cell frequency in the bone marrow of mice and promote progenitor cell differentiation

    Directory of Open Access Journals (Sweden)

    Sollars Vincent E

    2009-03-01

    Full Text Available Abstract Background Omega 3 fatty acids have been found to inhibit proliferation, induce apoptosis, and promote differentiation in various cell types. The processes of cell survival, expansion, and differentiation are of key importance in the regulation of hematopoiesis. We investigated the role of omega 3 fatty acids in controlling the frequency of various myeloid progenitor cells in the bone marrow of mice. Increased progenitor cell frequency and blocked differentiation are characteristics of hematopoietic disorders of the myeloid lineage, such as myeloproliferative diseases and myeloid leukemias. Results We found that increasing the proportion of omega 3 fatty acids relative to the proportion of omega 6 fatty acids in the diet caused increased differentiation and reduced the frequency of myeloid progenitor cells in the bone marrow of mice. Furthermore, this had no adverse effect on peripheral white blood cell counts. Conclusion Our results indicate that omega 3 fatty acids impact hematopoietic differentiation by reducing myeloid progenitor cell frequency in the bone marrow and promoting progenitor cell differentiation. Further exploration of this discovery could lead to the use of omega 3 fatty acids as a therapeutic option for patients that have various disorders of hematopoiesis.

  8. [Acute myeloid leukemia].

    Science.gov (United States)

    Tabuchi, Ken

    2007-02-01

    The annual incident rate of pediatric acute myeloid leukemia (AML) is now 10 per million in Japan, against 5 to 9 per million in the USA and Europe. Overall long-term survival has now been achieved for more than 50% of pediatric patients with AML in the USA and in Europe. The prognostic factors of pediatric AML were analyzed,and patients with AML were classified according to prognostic factors. The t(15;17), inv(16) and t(8;21) have emerged as predictors of good prognosis in children with AML. Monosomy 7, monosomy 5 and del (5 q) abnormalities showed a poor prognosis. In addition to chromosomal deletions, FLT 3/ITD identifies pediatric patients with a particularly poor prognosis. Clinical trials of AML feature intensive chemotherapy with or without subsequent stem cell transplantation. Risk group stratification is becoming increasingly important in planning AML therapy. APL can be distinguished from other subtypes of AML by virtue of its excellent response and overall outcome as a result of differentiation therapy with ATRA. Children with Down syndrome and AML have been shown to have a superior prognosis to AML therapy compared to other children with AML. The results of the Japan Cooperative Study Group protocol ANLL 91 was one of the best previously reported in the literature. With the consideration of quality of life (QOL), risk-adapted therapy was introduced in the AML 99 trial conducted by the Japanese Childhood AML Cooperative Study Group. A high survival rate of 79% at 3 years was achieved for childhood de novo AML in the AML 99 trial. To evaluate the efficacy and safety of the treatment strategy according to risk stratification based on leukemia cell biology and response to the initial induction therapy in children with AML, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) has organized multi-center phase II trials in children with newly diagnosed AML.

  9. Calorie restriction reduces the incidence of radiation-induced myeloid leukemia and spontaneous tumor

    International Nuclear Information System (INIS)

    Yoshida, Kazuko

    1999-01-01

    The host-defense mechanisms against cancers are known to be modulated by changing the environmental factor(s). The spontaneous incidence of myeloid leukemia is about 1% in C3H/He mice, and the incidence increases up to 23.3% when a single dose of radiation, 3 Gy X-ray, is exposed to a whole-body. Since calorie restriction was known to reduce the incidence of spontaneous tumors, a question as to whether such radiation induced-increase of myeloid leukemia would be also decreased by calorie restriction, was aimed to answer to elucidate possible mechanism of radiation-induced myeloid leukemia. By the calorie restriction, the incidence of myeloid leukemia was significantly decreased; it was reduced to 7.9% and 10.7% when restriction was started before (6 weeks old) and after (10 weeks old) irradiation, respectively. In addition, the latent period of the myeloid leukemia in the groups for calorie restriction was significantly extended at a greater extent as compared with the control diet groups. Number of hematopoietic stem cells, the possible target cells for radiation-induced leukemias, in the groups for the calorie restriction demonstrated a significant decrease, especially in the spleen, as compared with that in the control, when the evaluation was made at the time of radiation exposure. Then, we examined whether the decreased number of target cells at the time of exposure is caused by the reduction of radiation-induced myeloid leukemia with caloric restriction. The third restricted groups were fed 65 kcal diet (restricted diet) for the first 4 weeks i.e. from 6 weeks to 10 weeks old, then, the mice were fed with control diet after radiation. The incidence of myeloid leukemia in this group was slightly decreased but did not show statistically significance. Therefore, the caloric restriction seems to be more effective in the promotion stage than the initiation stage on radiation-induced leukemogenesis. It is well known that C3H/He mice develop hepatoma spontaneously

  10. Electrochemotherapy increases local control after incomplete ...

    African Journals Online (AJOL)

    Ibrahim Eldaghayes

    2016-11-24

    Nov 24, 2016 ... The treatment was well tolerated, and the patient is still disease free after 12 months. ECT resulted in improved local control and should be considered among the available adjuvant treatments in equines carrying soft tissue tumors. Keywords: Cisplatin, Electrochemotherapy, Equine, Fibrosarcoma.

  11. How Is Chronic Myeloid Leukemia Diagnosed?

    Science.gov (United States)

    ... Myeloid Leukemia? More In Chronic Myeloid Leukemia About Chronic Myeloid Leukemia Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treatment After Treatment Back To Top Imagine a world ...

  12. Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?

    Directory of Open Access Journals (Sweden)

    Federico Mosna

    2017-06-01

    Full Text Available Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of the disease, as the final product of the drug schedule, dose intensity, biodistribution, and the pharmakogenetic profile of the patient. There is now consistent evidence for the prognostic power of minimal residual disease evaluation in acute myeloid leukemia, which is complementary to the baseline prognostic assessment of the disease. The focus for its use is therefore shifting to individualize treatment based on a deeper evaluation of chemosensitivity and residual tumor burden. In this review, we will summarize the results of the major clinical studies evaluating minimal residual disease in acute myeloid leukemia in adults in recent years and address the technical and practical issues still hampering the spread of these techniques outside controlled clinical trials. We will also briefly speculate on future developments and offer our point of view, and a word of caution, on the present use of minimal residual disease measurements in “real-life” practice. Still, as final standardization and diffusion of the methods are sorted out, we believe that minimal residual disease will soon become the new standard for evaluating response in the treatment of acute myeloid leukemia.

  13. Exploring the acute myeloid leukaemias

    Directory of Open Access Journals (Sweden)

    TB Thapa

    2013-10-01

    Full Text Available The acute myeloid leukemias are genetically a diverse group of neoplasm with varied clinical behavior and response to treatment. Advances in immunophenotyping, cytogenetics and molecular genetics have resulted in better understanding of their genesis. Risk stratification of different variants is now emerging. Therapy strategies are now increasingly being developed considering the inherent biological behavior of the different subtypes. It is anticipated that in the future, deeper secrets of these once fatal diseases will be unraveled by advances in newer genomic techniques. It is hoped that future use of gene specific tailored therapy and strategies will result in longer survival in cases showing poorer prognosis at present. DOI: http://dx.doi.org/10.3126/jpn.v3i6.9001 Journal of Pathology of Nepal (2013 Vol. 3, 497-501

  14. Increased chemotaxis and activity of circulatory myeloid progenitor cells may contribute to enhanced osteoclastogenesis and bone loss in the C57BL/6 mouse model of collagen-induced arthritis.

    Science.gov (United States)

    Ikić Matijašević, M; Flegar, D; Kovačić, N; Katavić, V; Kelava, T; Šućur, A; Ivčević, S; Cvija, H; Lazić Mosler, E; Kalajzić, I; Marušić, A; Grčević, D

    2016-12-01

    Our study aimed to determine the functional activity of different osteoclast progenitor (OCP) subpopulations and signals important for their migration to bone lesions, causing local and systemic bone resorption during the course of collagen-induced arthritis in C57BL/6 mice. Arthritis was induced with chicken type II collagen (CII), and assessed by clinical scoring and detection of anti-CII antibodies. We observed decreased trabecular bone volume of axial and appendicular skeleton by histomorphometry and micro-computed tomography as well as decreased bone formation and increased bone resorption rate in arthritic mice in vivo. In the affected joints, bone loss was accompanied with severe osteitis and bone marrow hypercellularity, coinciding with the areas of active osteoclasts and bone erosions. Flow cytometry analysis showed increased frequency of putative OCP cells (CD3 - B220 - NK1.1 - CD11b -/lo CD117 + CD115 + for bone marrow and CD3 - B220 - NK1.1 - CD11b + CD115 + Gr-1 + for peripheral haematopoietic tissues), which exhibited enhanced differentiation potential in vitro. Moreover, the total CD11b + population was expanded in arthritic mice as well as CD11b + F4/80 + macrophage, CD11b + NK1.1 + natural killer cell and CD11b + CD11c + myeloid dendritic cell populations in both bone marrow and peripheral blood. In addition, arthritic mice had increased expression of tumour necrosis factor-α, interleukin-6, CC chemokine ligand-2 (Ccl2) and Ccl5, with increased migration and differentiation of circulatory OCPs in response to CCL2 and, particularly, CCL5 signals. Our study characterized the frequency and functional properties of OCPs under inflammatory conditions associated with arthritis, which may help to clarify crucial molecular signals provided by immune cells to mediate systemically enhanced osteoresorption. © 2016 British Society for Immunology.

  15. Dynamics of myeloid cell populations during relapse-preventive immunotherapy in acute myeloid leukemia.

    Science.gov (United States)

    Rydström, Anna; Hallner, Alexander; Aurelius, Johan; Sander, Frida Ewald; Bernson, Elin; Kiffin, Roberta; Thoren, Fredrik Bergh; Hellstrand, Kristoffer; Martner, Anna

    2017-08-01

    Relapse of leukemia in the postchemotherapy phase contributes to the poor prognosis and survival in patients with acute myeloid leukemia (AML). In an international phase IV trial (ClinicalTrials.gov; NCT01347996), 84 patients with AML in first complete remission who had not undergone transplantation received immunotherapy with histamine dihydrochloride (HDC) and low-dose IL-2 with the aim of preventing relapse. The dynamics of myeloid cell counts and expression of activation markers was assessed before and after cycles of immunotherapy and correlated with clinical outcome in terms of relapse risk and survival. During cycles, a pronounced increase in blood eosinophil counts was observed along with a reduction in monocyte and neutrophil counts. A strong reduction of blood monocyte counts during the first HDC/IL-2 treatment cycle predicted leukemia-free survival. The HDC component of the immunotherapy exerts agonist activity at histamine type 2 receptors (H2Rs) that are expressed by myeloid cells. It was observed that the density of H 2 R expression in blood monocytes increased during cycles of immunotherapy and that high monocyte H 2 R expression implied reduced relapse risk and improved overall survival. Several other activation markers, including HLA-DR, CD86, and CD40, were induced in monocytes and dendritic cells during immunotherapy but did not predict clinical outcome. In addition, expression of HLA-ABC increased in all myeloid populations during therapy. A low expression of HLA-ABC was associated with reduced relapse risk. These results suggest that aspects of myeloid cell biology may impact clinical benefit of relapse-preventive immunotherapy in AML. © Society for Leukocyte Biology.

  16. Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990-2005

    International Nuclear Information System (INIS)

    Kaplan, Henry G; Malmgren, Judith A; Atwood, Mary K

    2011-01-01

    Our objective was to measure myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) risk associated with radiation and/or chemotherapy breast cancer (BC) treatment. Our study cohort was composed of BC patients diagnosed from 1990 to 2005 and followed up for blood disorders, mean length of follow up = 7.17 years, range 2-18 years. 5790 TNM stage 0-III patients treated with surgery alone, radiation and/or chemotherapy were included. Patients without surgery (n = 111), with stem cell transplantation (n = 98), unknown or non-standard chemotherapy regimens (n = 94), lost to follow up (n = 66) or 'cancer status unknown' (n = 67) were excluded. Rates observed at our community based cancer care institution were compared to SEER incidence data for rate ratio (RR) calculations. 17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period, crude rate .29% (95% CI = .17, .47), SEER comparison RR = 3.94 (95% CI = 2.34, 6.15). The RR of MDS in patients age < 65 comparing our cohort incidence to SEER incidence data was 10.88 (95% CI = 3.84, 24.03) and the RR of AML in patients age < 65 was 5.32 (95% CI = 1.31, 14.04). No significant increased risk of MDS or AML was observed in women ≥ 65 or the surgery/chemotherapy-only group. A RR of 3.32 (95% CI = 1.42, 6.45) was observed in the surgery/radiation-only group and a RR of 6.32 (95% CI = 3.03, 11.45) in the surgery/radiation/chemotherapy group. 3 out of 10 MDS cases died of disease at an average 3.8 months post diagnosis and five of seven AML cases died at an average 9 months post diagnosis. An elevated rate of MDS and AML was observed among breast cancer patients < 65, those treated with radiation and those treated with radiation and chemotherapy compared to available population incidence data. Although a small number of patients are affected, leukemia risk associated with treatment and younger age is significant

  17. Neurological Complications Of Chronic Myeloid Leukaemia: Any ...

    African Journals Online (AJOL)

    , of the neurological deficits complicating chronic myeloid leukaemia. Method: Using patients\\' case folders and haematological malignancy register all cases of chronic myeloid leukaemia seen in Jos University Teaching Hospital between July ...

  18. Myeloid Heme Oxygenase-1 Regulates the Acute Inflammatory Response to Zymosan in the Mouse Air Pouch

    Directory of Open Access Journals (Sweden)

    Rita Brines

    2018-01-01

    Full Text Available Heme oxygenase-1 (HO-1 is induced by many stimuli to modulate the activation and function of different cell types during innate immune responses. Although HO-1 has shown anti-inflammatory effects in different systems, there are few data on the contribution of myeloid HO-1 and its role in inflammatory processes is not well understood. To address this point, we have used HO-1M-KO mice with myeloid-restricted deletion of HO-1 to specifically investigate its influence on the acute inflammatory response to zymosan in vivo. In the mouse air pouch model, we have shown an exacerbated inflammation in HO-1M-KO mice with increased neutrophil infiltration accompanied by high levels of inflammatory mediators such as interleukin-1β, tumor necrosis factor-α, and prostaglandin E2. The expression of the degradative enzyme matrix metalloproteinase-3 (MMP-3 was also enhanced. In addition, we observed higher levels of serum MMP-3 in HO-1M-KO mice compared with control mice, suggesting the presence of systemic inflammation. Altogether, these findings demonstrate that myeloid HO-1 plays an anti-inflammatory role in the acute response to zymosan in vivo and suggest the interest of this target to regulate inflammatory processes.

  19. Economic Effects of Increased Control Zone Sizes in Conflict Resolution

    Science.gov (United States)

    Datta, Koushik

    1998-01-01

    A methodology for estimating the economic effects of different control zone sizes used in conflict resolutions between aircraft is presented in this paper. The methodology is based on estimating the difference in flight times of aircraft with and without the control zone, and converting the difference into a direct operating cost. Using this methodology the effects of increased lateral and vertical control zone sizes are evaluated.

  20. Outcomes following splenectomy in patients with myeloid neoplasms.

    Science.gov (United States)

    Rialon, Kristy L; Speicher, Paul J; Ceppa, Eugene P; Rendell, Victoria R; Vaslef, Steven N; Beaven, Anne; Tyler, Douglas S; Blazer, Dan G

    2015-03-15

    Myeloid neoplasms are classified into five major categories. These patients may develop splenomegaly and require splenectomy to alleviate mechanical symptoms, to ameliorate transfusion-dependent cytopenias, or to enhance stem cell transplantation. The objective of this study was to determine which clinical variables significantly impacted morbidity, mortality, and survival in patients with myeloid neoplasms undergoing splenectomy, and to determine if operative outcomes have improved over time. The records of all patients with myeloid neoplasms undergoing splenectomy from 1993 to 2010 were retrospectively reviewed. Eighty-nine patients (n = 89) underwent splenectomy for myeloid neoplasms. Over half of patients who had symptoms preoperatively had resolution of their symptoms post-splenectomy. The morbidity rate was 38%, with the most common complications being bleeding (14%) or infection (20%). Thirty-day mortality rate was 18% and median survival after splenectomy was 278 days. Decreased survival was associated with a diagnosis of myelodysplastic syndrome/myeloproliferative neoplasm, anemia, abnormal white blood cell count, and hypoalbuminemia. Patients who underwent stem cell transplantation did not show an increased risk for morbidity or mortality. Patients with myeloid neoplasms have a poor prognosis after splenectomy and the decision to operate is a difficult one, associated with high morbidity and mortality. © 2014 Wiley Periodicals, Inc.

  1. Techniques for increasing the reliability of accelerator control system electronics

    International Nuclear Information System (INIS)

    Utterback, J.

    1993-09-01

    As the physical size of modern accelerators becomes larger and larger, the number of required control system circuit boards increases, and the probability of one of those circuit boards failing while in service also increases. In order to do physics, the experimenters need the accelerator to provide beam reliably with as little down time as possible. With the advent of colliding beams physics, reliability becomes even more important due to the fact that a control system failure can cause the loss of painstakingly produced antiprotons. These facts prove the importance of keeping reliability in mind when designing and maintaining accelerator control system electronics

  2. Exercising self-control increases relative left frontal cortical activation.

    Science.gov (United States)

    Schmeichel, Brandon J; Crowell, Adrienne; Harmon-Jones, Eddie

    2016-02-01

    Self-control refers to the capacity to override or alter a predominant response tendency. The current experiment tested the hypothesis that exercising self-control temporarily increases approach motivation, as revealed by patterns of electrical activity in the prefrontal cortex. Participants completed a writing task that did vs did not require them to exercise self-control. Then they viewed pictures known to evoke positive, negative or neutral affect. We assessed electroencephalographic (EEG) activity while participants viewed the pictures, and participants reported their trait levels of behavioral inhibition system (BIS) and behavioral activation system (BAS) sensitivity at the end of the study. We found that exercising (vs not exercising) self-control increased relative left frontal cortical activity during picture viewing, particularly among individuals with relatively higher BAS than BIS, and particularly during positive picture viewing. A similar but weaker pattern emerged during negative picture viewing. The results suggest that exercising self-control temporarily increases approach motivation, which may help to explain the aftereffects of self-control (i.e. ego depletion). © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  3. Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy

    Directory of Open Access Journals (Sweden)

    Leslie Chavez-Galan

    2017-08-01

    Full Text Available Pleural tuberculosis (TB is a form of extra-pulmonary TB observed in patients infected with Mycobacterium tuberculosis. Accumulation of myeloid-derived suppressor cells (MDSC has been observed in animal models of TB and in human patients but their role remains to be fully elucidated. In this study, we analyzed the role of transmembrane TNF (tmTNF in the accumulation and function of MDSC in the pleural cavity during an acute mycobacterial infection. Mycobacterium bovis BCG-induced pleurisy was resolved in mice expressing tmTNF, but lethal in the absence of tumor necrosis factor. Pleural infection induced MDSC accumulation in the pleural cavity and functional MDSC required tmTNF to suppress T cells as did pleural wild-type MDSC. Interaction of MDSC expressing tmTNF with CD4 T cells bearing TNF receptor 2 (TNFR2, but not TNFR1, was required for MDSC suppressive activity on CD4 T cells. Expression of tmTNF attenuated Th1 cell-mediated inflammatory responses generated by the acute pleural mycobacterial infection in association with effective MDSC expressing tmTNF and interacting with CD4 T cells expressing TNFR2. In conclusion, this study provides new insights into the crucial role played by the tmTNF/TNFR2 pathway in MDSC suppressive activity required during acute pleural infection to attenuate excessive inflammation generated by the infection.

  4. Controlled mass pollination in loblolly pine to increase genetic gains

    Science.gov (United States)

    F.E. Bridgwater; D.L. Bramlett; T.D. Byram; W.J. Lowe

    1998-01-01

    Controlled mass pollination (CMP) is one way to increase genetic gains from traditional wind-pollinated seed orchards. Methodology is under development by several forestry companies in the southern USA. Costs of CMP depend on the efficient installation, pollination, and removal of inexpensive paper bags. Even in pilot-scale studies these costs seem reasonable. Net...

  5. E-learning: controlling costs and increasing value.

    Science.gov (United States)

    Walsh, Kieran

    2015-04-01

    E-learning now accounts for a substantial proportion of medical education provision. This progress has required significant investment and this investment has in turn come under increasing scrutiny so that the costs of e-learning may be controlled and its returns maximised. There are multiple methods by which the costs of e-learning can be controlled and its returns maximised. This short paper reviews some of those methods that are likely to be most effective and that are likely to save costs without compromising quality. Methods might include accessing free or low-cost resources from elsewhere; create short learning resources that will work on multiple devices; using open source platforms to host content; using in-house faculty to create content; sharing resources between institutions; and promoting resources to ensure high usage. Whatever methods are used to control costs or increase value, it is most important to evaluate the impact of these methods.

  6. Lumbar Myeloid Cell Trafficking into Locomotor Networks after Thoracic Spinal Cord Injury

    Science.gov (United States)

    Hansen, Christopher N.; Norden, Diana M.; Faw, Timothy D.; Deibert, Rochelle; S.Wohleb, Eric; Sheridan, John F.; P.Godbout, Jonathan; Basso, D. Michele

    2016-01-01

    Spinal cord injury (SCI) promotes inflammation along the neuroaxis that jeopardizes plasticity, intrinsic repair and recovery. While inflammation at the injury site is well-established, less is known within remote spinal networks. The presence of bone marrow-derived immune (myeloid) cells in these areas may further impede functional recovery. Previously, high levels of the gelatinase, matrix metalloproteinase-9 (MMP-9) occurred within the lumbar enlargement after thoracic SCI and impeded activity-dependent recovery. Since SCI-induced MMP-9 potentially increases vascular permeability, myeloid cell infiltration may drive inflammatory toxicity in locomotor networks. Therefore, we examined neurovascular reactivity and myeloid cell infiltration in the lumbar cord after thoracic SCI. We show evidence of region-specific recruitment of myeloid cells into the lumbar but not cervical region. Myeloid infiltration occurred with concomitant increases in chemoattractants (CCL2) and cell adhesion molecules (ICAM-1) around lumbar vasculature 24 hours and 7 days post injury. Bone marrow GFP chimeric mice established robust infiltration of bone marrow-derived myeloid cells into the lumbar gray matter 24 hours after SCI. This cell infiltration occurred when the blood-spinal cord barrier was intact, suggesting active recruitment across the endothelium. Myeloid cells persisted as ramified macrophages at 7 days post injury in parallel with increased inhibitory GAD67 labeling. Importantly, macrophage infiltration required MMP-9. PMID:27191729

  7. Plasma control system upgrade and increased plasma stability in NSTX

    Energy Technology Data Exchange (ETDEWEB)

    Mastrovito, D., E-mail: dmastrovito@pppl.go [Princeton Plasma Physics Laboratory, P.O. Box 451 Princeton, NJ 08543 (United States); Gates, D.; Gerhard, S.; Lawson, J.; Ludescher-Furth, C.; Marsala, R. [Princeton Plasma Physics Laboratory, P.O. Box 451 Princeton, NJ 08543 (United States)

    2010-07-15

    Plasma control on the National Spherical Torus Experiment (NSTX) was previously accomplished using eight 333 MHz G4 processors built by Sky computers. Several planned improvements and additional control algorithms required significant upgrades to our real-time control computers and real-time data acquisition infrastructure. Several in-house modules have been designed and implemented including: the digital time stamp module (DITS) and for digital/analog front panel data port (FPDP) output, the FPDP output module digital/analog (FOMD/A). Standard Linux based Intel computers perform the real-time control tasks and InfiniBand as been employed for communication between a user-accessible 'host' server and the real-time computer. In addition to several independent real-time processes the General Atomics developed PCS (Bell (2006) ) system infrastructure continues to be used on NSTX. While maintaining previous functionality, improvements in the control system software include: an RWM feedback algorithm, beta feedback NBI control, more comprehensive error logging and trapping, more user-friendly interface, more complete archiving and restoring functionality, and better status reporting and diagnostic tools. Once completed, we succeeded in increasing overall plasma stability and decreasing control system latency by several times.

  8. Therapies for acute myeloid leukemia: vosaroxin

    Directory of Open Access Journals (Sweden)

    Sayar H

    2017-08-01

    Full Text Available Hamid Sayar,1 Parvaneh Bashardoust2 1Indiana University Simon Cancer Center, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; 2Oceania University of Medicine, OUM-North America, Indianapolis, IN, USA Abstract: Vosaroxin, a quinolone-derivative chemotherapeutic agent, was considered a promising drug for the treatment of acute myeloid leukemia (AML. Early-stage clinical trials with this agent led to a large randomized double-blind placebo-controlled study of vosaroxin in combination with intermediate-dose cytarabine for the treatment of relapsed or refractory AML. The study demonstrated better complete remission rates with vosaroxin, but there was no statistically significant overall survival benefit in the whole cohort. A subset analysis censoring patients who had undergone allogeneic stem cell transplantation, however, revealed a modest but statistically significant improvement in overall survival particularly among older patients. This article reviews the data available on vosaroxin including clinical trials in AML and offers an analysis of findings of these studies as well as the current status of vosaroxin. Keywords: AML, acute myeloid leukemia, vosaroxin, SNS-595, cytarabine

  9. Programming adaptive control to evolve increased metabolite production.

    Science.gov (United States)

    Chou, Howard H; Keasling, Jay D

    2013-01-01

    The complexity inherent in biological systems challenges efforts to rationally engineer novel phenotypes, especially those not amenable to high-throughput screens and selections. In nature, increased mutation rates generate diversity in a population that can lead to the evolution of new phenotypes. Here we construct an adaptive control system that increases the mutation rate in order to generate diversity in the population, and decreases the mutation rate as the concentration of a target metabolite increases. This system is called feedback-regulated evolution of phenotype (FREP), and is implemented with a sensor to gauge the concentration of a metabolite and an actuator to alter the mutation rate. To evolve certain novel traits that have no known natural sensors, we develop a framework to assemble synthetic transcription factors using metabolic enzymes and construct four different sensors that recognize isopentenyl diphosphate in bacteria and yeast. We verify FREP by evolving increased tyrosine and isoprenoid production.

  10. New degradation call admission control for increasing WCDMA system capacity

    Institute of Scientific and Technical Information of China (English)

    Liu Ningqing; Lu Zhi; Gu Xuemai

    2006-01-01

    Propose a new degradation call admission control(DCAC)scheme, which can be used in wideband code division multiple access communication system. So-called degradation is that non-real time call has the characteristic of variable bit rate, so decreasing its bit rate can reduce the load of the system, consequently the system can admit new call which should be blocked when the system is close to full load, therefore new call's access probability increases. This paper brings forward design project and does system simulation, simulation proves that DCAC can effectively decrease calls' blocking probability and increase the total number of the on-line users.

  11. Myeloid differentiation factor 88-deficient bone marrow cells improve Alzheimer's disease-related symptoms and pathology

    NARCIS (Netherlands)

    Hao, W.; Liu, Y.; Liu, S.; Walter, S.; Grimm, M.O.; Kiliaan, A.J.; Penke, B.; Hartmann, T.; Rube, C.E.; Menger, M.D.; Fassbender, K.

    2011-01-01

    Alzheimer's disease is characterized by extracellular deposits of amyloid beta peptide in the brain. Increasing evidence suggests that amyloid beta peptide injures neurons both directly and indirectly by triggering neurotoxic innate immune responses. Myeloid differentiation factor 88 is the key

  12. Minimal Residual Disease in Acute Myeloid Leukemia

    Science.gov (United States)

    Hourigan, Christopher S.; Karp, Judith E.

    2014-01-01

    Technological advances in the laboratory have lead to substantial improvements in clinical decision-making by the use of pre-treatment prognostic risk stratification factors in acute myeloid leukemia (AML). Unfortunately similar progress has not been made in treatment response criteria, with the definition of “complete remission” in AML largely unchanged for over half a century. Several recent clinical trials have demonstrated that higher sensitivity measurements of residual disease burden during or after treatment can be performed, that results are predictive for clinical outcome and can be used to improve outcomes by guiding additional therapeutic intervention to patients in clinical complete remission but at increased relapse risk. We review here these recent trials, the characteristics and challenges of the modalities currently used to detect minimal residual disease (MRD), and outline opportunities to both refine detection and better clinically utilize MRD measurements. MRD measurement is already the standard of care in other myeloid malignancies such as chronic myelogenous leukemia (CML) and acute promyelocytic leukemia (APL). It is our belief that response criteria for non-APL AML should be updated to include assessment for molecular complete remission (mCR) and that recommendations for post-consolidation surveillance should include regular monitoring for molecular relapse as a standard of care. PMID:23799371

  13. Modeling Myeloid Malignancies Using Zebrafish

    Directory of Open Access Journals (Sweden)

    Kathryn S. Potts

    2017-12-01

    Full Text Available Human myeloid malignancies represent a substantial disease burden to individuals, with significant morbidity and death. The genetic underpinnings of disease formation and progression remain incompletely understood. Large-scale human population studies have identified a high frequency of potential driver mutations in spliceosomal and epigenetic regulators that contribute to malignancies, such as myelodysplastic syndromes (MDS and leukemias. The high conservation of cell types and genes between humans and model organisms permits the investigation of the underlying mechanisms of leukemic development and potential therapeutic testing in genetically pliable pre-clinical systems. Due to the many technical advantages, such as large-scale screening, lineage-tracing studies, tumor transplantation, and high-throughput drug screening approaches, zebrafish is emerging as a model system for myeloid malignancies. In this review, we discuss recent advances in MDS and leukemia using the zebrafish model.

  14. PROGRESS IN ACUTE MYELOID LEUKEMIA

    Science.gov (United States)

    Kadia, Tapan M.; Ravandi, Farhad; O’Brien, Susan; Cortes, Jorge; Kantarjian, Hagop M.

    2014-01-01

    Significant progress has been made in the treatment of acute myeloid leukemia (AML). Steady gains in clinical research and a renaissance of genomics in leukemia have led to improved outcomes. The recognition of tremendous heterogeneity in AML has allowed individualized treatments of specific disease entities within the context of patient age, cytogenetics, and mutational analysis. The following is a comprehensive review of the current state of AML therapy and a roadmap of our approach to these distinct disease entities. PMID:25441110

  15. Acute myeloid leukemia risk by industry and occupation.

    Science.gov (United States)

    Tsai, Rebecca J; Luckhaupt, Sara E; Schumacher, Pam; Cress, Rosemary D; Deapen, Dennis M; Calvert, Geoffrey M

    2014-11-01

    Acute myeloid leukemia (AML) is the most common type of leukemia found in adults. Identifying jobs that pose a risk for AML may be useful for identifying new risk factors. A matched case-control analysis was conducted using California Cancer Registry data from 1988 to 2007. This study included 8999 cases of AML and 24 822 controls. Industries with a statistically significant increased AML risk were construction (matched odds ratio [mOR] = 1.13); crop production (mOR = 1.41); support activities for agriculture and forestry (mOR = 2.05); and animal slaughtering and processing (mOR = 2.09). Among occupations with a statistically significant increased AML risk were miscellaneous agricultural workers (mOR = 1.76); fishers and related fishing workers (mOR = 2.02); nursing, psychiatric and home health aides (mOR = 1.65); and janitors and building cleaners (mOR = 1.54). Further investigation is needed to confirm study findings and to identify specific exposures responsible for the increased risks.

  16. Female gonadal shielding with automatic exposure control increases radiation risks

    Energy Technology Data Exchange (ETDEWEB)

    Kaplan, Summer L.; Zhu, Xiaowei [Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (United States); Magill, Dennise; Felice, Marc A. [University of Pennsylvania, Environmental Health and Radiation Safety, Philadelphia, PA (United States); Xiao, Rui [University of Pennsylvania, Department of Biostatistics and Epidemiology, Philadelphia, PA (United States); Ali, Sayed [Temple University Hospital, Department of Radiology, Philadelphia, PA (United States)

    2018-02-15

    Gonadal shielding remains common, but current estimates of gonadal radiation risk are lower than estimated risks to colon and stomach. A female gonadal shield may attenuate active automatic exposure control (AEC) sensors, resulting in increased dose to colon and stomach as well as to ovaries outside the shielded area. We assess changes in dose-area product (DAP) and absorbed organ dose when female gonadal shielding is used with AEC for pelvis radiography. We imaged adult and 5-year-old equivalent dosimetry phantoms using pelvis radiograph technique with AEC in the presence and absence of a female gonadal shield. We recorded DAP and mAs and measured organ absorbed dose at six internal sites using film dosimetry. Female gonadal shielding with AEC increased DAP 63% for the 5-year-old phantom and 147% for the adult phantom. Absorbed organ dose at unshielded locations of colon, stomach and ovaries increased 21-51% in the 5-year-old phantom and 17-100% in the adult phantom. Absorbed organ dose sampled under the shield decreased 67% in the 5-year-old phantom and 16% in the adult phantom. Female gonadal shielding combined with AEC during pelvic radiography increases absorbed dose to organs with greater radiation sensitivity and to unshielded ovaries. Difficulty in proper use of gonadal shields has been well described, and use of female gonadal shielding may be inadvisable given the risks of increasing radiation. (orig.)

  17. Female gonadal shielding with automatic exposure control increases radiation risks

    International Nuclear Information System (INIS)

    Kaplan, Summer L.; Zhu, Xiaowei; Magill, Dennise; Felice, Marc A.; Xiao, Rui; Ali, Sayed

    2018-01-01

    Gonadal shielding remains common, but current estimates of gonadal radiation risk are lower than estimated risks to colon and stomach. A female gonadal shield may attenuate active automatic exposure control (AEC) sensors, resulting in increased dose to colon and stomach as well as to ovaries outside the shielded area. We assess changes in dose-area product (DAP) and absorbed organ dose when female gonadal shielding is used with AEC for pelvis radiography. We imaged adult and 5-year-old equivalent dosimetry phantoms using pelvis radiograph technique with AEC in the presence and absence of a female gonadal shield. We recorded DAP and mAs and measured organ absorbed dose at six internal sites using film dosimetry. Female gonadal shielding with AEC increased DAP 63% for the 5-year-old phantom and 147% for the adult phantom. Absorbed organ dose at unshielded locations of colon, stomach and ovaries increased 21-51% in the 5-year-old phantom and 17-100% in the adult phantom. Absorbed organ dose sampled under the shield decreased 67% in the 5-year-old phantom and 16% in the adult phantom. Female gonadal shielding combined with AEC during pelvic radiography increases absorbed dose to organs with greater radiation sensitivity and to unshielded ovaries. Difficulty in proper use of gonadal shields has been well described, and use of female gonadal shielding may be inadvisable given the risks of increasing radiation. (orig.)

  18. Female gonadal shielding with automatic exposure control increases radiation risks.

    Science.gov (United States)

    Kaplan, Summer L; Magill, Dennise; Felice, Marc A; Xiao, Rui; Ali, Sayed; Zhu, Xiaowei

    2018-02-01

    Gonadal shielding remains common, but current estimates of gonadal radiation risk are lower than estimated risks to colon and stomach. A female gonadal shield may attenuate active automatic exposure control (AEC) sensors, resulting in increased dose to colon and stomach as well as to ovaries outside the shielded area. We assess changes in dose-area product (DAP) and absorbed organ dose when female gonadal shielding is used with AEC for pelvis radiography. We imaged adult and 5-year-old equivalent dosimetry phantoms using pelvis radiograph technique with AEC in the presence and absence of a female gonadal shield. We recorded DAP and mAs and measured organ absorbed dose at six internal sites using film dosimetry. Female gonadal shielding with AEC increased DAP 63% for the 5-year-old phantom and 147% for the adult phantom. Absorbed organ dose at unshielded locations of colon, stomach and ovaries increased 21-51% in the 5-year-old phantom and 17-100% in the adult phantom. Absorbed organ dose sampled under the shield decreased 67% in the 5-year-old phantom and 16% in the adult phantom. Female gonadal shielding combined with AEC during pelvic radiography increases absorbed dose to organs with greater radiation sensitivity and to unshielded ovaries. Difficulty in proper use of gonadal shields has been well described, and use of female gonadal shielding may be inadvisable given the risks of increasing radiation.

  19. Hoxa9 and Hoxa10 induce CML myeloid blast crisis development through activation of Myb expression.

    Science.gov (United States)

    Negi, Vijay; Vishwakarma, Bandana A; Chu, Su; Oakley, Kevin; Han, Yufen; Bhatia, Ravi; Du, Yang

    2017-11-17

    Mechanisms underlying the progression of Chronic Myeloid Leukemia (CML) from chronic phase to myeloid blast crisis are poorly understood. Our previous studies have suggested that overexpression of SETBP1 can drive this progression by conferring unlimited self-renewal capability to granulocyte macrophage progenitors (GMPs). Here we show that overexpression of Hoxa9 or Hoxa10 , both transcriptional targets of Setbp1 , is also sufficient to induce self-renewal of primary myeloid progenitors, causing their immortalization in culture. More importantly, both are able to cooperate with BCR/ABL to consistently induce transformation of mouse GMPs and development of aggressive leukemias resembling CML myeloid blast crisis, suggesting that either gene can drive CML progression by promoting the self-renewal of GMPs. We further identify Myb as a common critical target for Hoxa9 and Hoxa10 in inducing self-renewal of myeloid progenitors as Myb knockdown significantly reduced colony-forming potential of myeloid progenitors immortalized by the expression of either gene. Interestingly, Myb is also capable of immortalizing primary myeloid progenitors in culture and cooperating with BCR/ABL to induce leukemic transformation of mouse GMPs. Significantly increased levels of MYB transcript also were detected in all human CML blast crisis samples examined over chronic phase samples, further suggesting the possibility that MYB overexpression may play a prevalent role in driving human CML myeloid blast crisis development. In summary, our results identify overexpression of HOXA9 , HOXA10 , and MYB as critical drivers of CML progression, and suggest MYB as a key therapeutic target for inhibiting the self-renewal of leukemia-initiating cells in CML myeloid blast crisis patients.

  20. Worldwide increase in diabetes: implications for tuberculosis control

    Directory of Open Access Journals (Sweden)

    Fisher-Hoch SP

    2014-07-01

    Full Text Available Susan P Fisher-HochDivision of Epidemiology, Human Genetics and Environmental Science, University of Texas School of Public Health, Brownsville Campus, Brownsville, TX, USAAbstract: Diabetes presents a greater threat to global tuberculosis (TB control than previously appreciated, with risk of reversing the achievements of several decades. An estimated 382 million people worldwide currently have diabetes, half of whom are undiagnosed. Most live in low- and middle-income countries alongside many of the two billion individuals infected with TB. Though the frequency of TB in type 1 diabetes was known for centuries, only recently have we observed the tripling of TB in type 2 diabetes, most significantly in high-burden TB populations such as in Peru, Russia, and the People's Republic of China. In India diabetes is estimated to have increased TB cases by 46% between 1998 and 2008. Diabetes is a greater long-term threat to TB control than human immunodeficiency virus (HIV/acquired immunodeficiency syndrome (AIDS since ten-fold more people are affected by diabetes than HIV/AIDS in larger geographic areas. Diabetes in TB increases drug resistance, treatment failure, and mortality, and may increase the spread of drug-resistant strains. Delayed or missed diagnosis fuels transmission of TB and hinders control of diabetes. Tailored treatment for diabetes patients requires well-designed clinical trials. The World Health Organization (WHO framework for care and control of diabetes and TB needs improved screening strategies. Determination of how best to establish bi-directional screening is hampered by lack of affordable and reliable methods. Recommendations include education of health care providers, patients, and communities. Structured diabetes programs with registries and effective follow-up could be modeled on and communicate with existing TB programs. Vital research should address new diagnostic tools, lowering cost and evaluation of intervention

  1. Therapies for acute myeloid leukemia: vosaroxin.

    Science.gov (United States)

    Sayar, Hamid; Bashardoust, Parvaneh

    2017-01-01

    Vosaroxin, a quinolone-derivative chemotherapeutic agent, was considered a promising drug for the treatment of acute myeloid leukemia (AML). Early-stage clinical trials with this agent led to a large randomized double-blind placebo-controlled study of vosaroxin in combination with intermediate-dose cytarabine for the treatment of relapsed or refractory AML. The study demonstrated better complete remission rates with vosaroxin, but there was no statistically significant overall survival benefit in the whole cohort. A subset analysis censoring patients who had undergone allogeneic stem cell transplantation, however, revealed a modest but statistically significant improvement in overall survival particularly among older patients. This article reviews the data available on vosaroxin including clinical trials in AML and offers an analysis of findings of these studies as well as the current status of vosaroxin.

  2. An oral Hemokine™, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo

    Science.gov (United States)

    Faller, Douglas V.; Castaneda, Serguei A.; Zhou, Daohong; Vedamony, Merriline; Newburger, Peter E.; White, Gary L.; Kosanke, Stanley; Plett, P. Artur; Orschell, Christie M.; Boosalis, Michael S.; Perrine, Susan P.

    2017-01-01

    An oral therapeutic which reduces duration of cytopenias and is active following accidental radiation exposures is an unmet need in radiation countermeasures. Alpha methylhydrocinnamate (ST7) prolongs STAT-5 phosphorylation, reduces growth-factor dependency of multi-lineage cell lines, and stimulates erythropoiesis. Here, ST7 and its isomers were studied for their effects on myeloid progenitors and hematopoietic stem cells (HSCs) following radiation, in nonhuman primates, and murine irradiation models. Addition of ST7 or ST7-S increased CFU-GM production by 1.7-fold (p200/mm3 and neutropenia recovered in 6 days with ST7 treatment and 18 days in controls (p<0.05). In lethally-irradiated mice, marrow pathology at 15 days was hypocellular (10% cellularity) in controls, but normal (55–75% cellularity) with complete neutrophil maturation with ST7-S treatment. Following lethal irradiation, ST7, given orally for 4 days, reduced mortality, with 30% survival in ST7-animals vs 8% in controls, (p<0.05). Collectively, the studies indicate that ST7 and ST7-S enhance myeloid recovery post-radiation and merit further evaluation to accelerate hematologic recovery in conditions of radiation-related and other marrow hypoplasias. PMID:27888688

  3. Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways.

    Science.gov (United States)

    Haverkamp, Jessica M; Smith, Amber M; Weinlich, Ricardo; Dillon, Christopher P; Qualls, Joseph E; Neale, Geoffrey; Koss, Brian; Kim, Young; Bronte, Vincenzo; Herold, Marco J; Green, Douglas R; Opferman, Joseph T; Murray, Peter J

    2014-12-18

    Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Chronic Myeloid Leukemia

    Science.gov (United States)

    ... the survivors of the atomic-bomb blast in Japan. A slight increase in risk also occurs in ... 2013;14(14):1977-1986. National Comprehensive Cancer Network. Practice Guidelines ... oncology social workers, nurses and health educators who are available ...

  5. Genetics Home Reference: chronic myeloid leukemia

    Science.gov (United States)

    ... Central Quintás-Cardama A, Cortes JE. Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc. 2006 Jul;81(7):973-88. Review. Citation on PubMed Skorski T. Genetic mechanisms of chronic myeloid leukemia blastic transformation. Curr Hematol Malig Rep. 2012 Jun; ...

  6. Use of gamma radiation for increasing plant disease control efficacy

    International Nuclear Information System (INIS)

    Chamswarng, Chiradej; Intanoo, Wanwilai; Piadang, Nattayana

    2006-09-01

    Irradiation of Trichoderma harzianum with 0.5-8.0 k Gay of gamma ray revealed 41 strains resistant to 10 ppm propiconazole or benomyl fungicides and two strains (23/03-7 and 27/08-1) were resistant to 10 ppm of both fungicides. After these two mutant strains were repeatedly irradiated with gamma ray, 74 mutant strains were obtained. Among these, three mutant strains, used as seed treatment effectively protected tomato seedlings from the infection of Pythium apanidermatum with significantly higher surviving seedlings than the Pythium inoculated control. The higher root colonization of mutant strains was obtains from strains 03/7-113, 03-/7-114 and 08/1-11. Rice seeds (RD 17), previously soaked in water for 24 ht were placed in spore suspension of T. harzianum prepared from 1 kg of fresh culture of 81 mutant isolated derived from single or double irradiation with gamma ray in 50 1 of water for 30 min. Two mutants including 23/03-7 (derived from single irradiation) and 03/7-134 (derived from double irradiation) provided percentages of root colonization by 29.63 and 25.93, while growth-promoted roots were 12.48 and 12.65 cm in length. respectively. These two strains were tested in rice field by treating pre-soaked seeds with Trichoderma suspensions for 30 min and incubated for 24 hr before sowing. Detection of root colonization by T. harzianum at 35, 45 and 102 days after sowing revealed that all Trichoderma strains effectively colonized rice roots at all stages of growth, particularly two mutants completely colonized rice root at 102 days after sowing. After harvesting, a mutant strain 30/7-134 increased rice yield to the maximum level at 29.65% over a control, while the percentage of fertile-seeds and it's seed weight, total seed weight, fertile-seed weight were significantly higher than a control. However, all Trichoderma strains provided the potential increases of rice yield over a control. Strain 03/7-134 significantly reduced percentage of dirty-panicle diseased

  7. Genital ulcers as diagnostic clue for acute myeloid leukaemia.

    Science.gov (United States)

    Schröder, Sina D; Krause, Stefan W; Erfurt-Berge, Cornelia

    2018-04-23

    Acute myeloid leukaemia is a myeloid neoplasm with an extremely varying clinical appearance. Skin lesions are common for specific subtypes of acute myeloid leukaemia but are often misinterpreted. Here, we present a case of acute myeloid leukaemia in a young woman exhibiting genital ulcerations and gingival erosions. © 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

  8. Biologico-clinical significance of DNMT3A variants expression in acute myeloid leukemia.

    Science.gov (United States)

    Lin, Na; Fu, Wei; Zhao, Chen; Li, Bixin; Yan, Xiaojing; Li, Yan

    2017-12-09

    DNA methyltransferase 3A (DNMT3A) catalyzes de novo DNA methylation and plays important roles in the pathogenesis of acute myeloid leukemia. However, the expression status of DNMT3A variants in acute myeloid leukemia remains obscure. This study aimed to assess the expression levels of alternative splicing of DNMT3A variants and explore their roles in acute myeloid leukemia (AML). DNMT3A variants gene expression were assessed, measuring their effects on cell proliferation. In addition, the expression of DNMT3A variants were evaluated in acute myeloid leukemia patients. Four DNMT3A variants were identified, with DNMT3A1 and DNMT3A2V found to be dominant in acute myeloid leukemia cell lines. Moreover, DNMT3A2V overexpression delayed cell proliferation; while, DNMT3A2V R882H mutation promoted cell proliferation. Further, DNMT3A1 and DNMT3A2V were detected in newly diagnosed acute myeloid leukemia (AML) patients and controls with non-malignant hematological disease, with DNMT3A2V significantly up-regulated in AML patients. The main transcript switched from DNMT3A1 to DNMT3A2V in some patients, especially the low risk group based on the NCCN 2016 guidelines. These findings suggest that DNMT3A1 and DNMT3A2V are the main variants in acute myeloid leukemia with different clinical association, and might play important roles in the pathophysiology of acute myeloid leukemia. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Synchronous Occurance of Acute Myeloid Leukemia and Rhabdomyosarcoma.

    Science.gov (United States)

    Jayasudha, A V; Nair, Rekha A; Renu, S; Binitha, R; Reghu, K S; Kusumakumary, P

    2015-09-01

    Metachronous primary distinct tumors are frequently and increasingly encountered in oncology clinical practice of recent times, but synchronous tumours are still a rarity. We report an unusual case of a 2 year old male child who had synchronous occurrence of rhabdomyosarcoma of pelvis and acute myeloid leukemia.Our search of literature suggests that this may be the first reported case of simultaneous occurrence of these two malignancies.

  10. Fighting with Fires: Decentralize Control to Increase Responsiveness

    National Research Council Canada - National Science Library

    Johnson, Robert

    2001-01-01

    .... The examination of theory explains how the Army's centralized control of fires to facilitate massing of fires, coupled with a poorly developed digital fire control system are the root causes of failure...

  11. The Role of Control System in Increasing Corporate social Performance: The Use of Levers of Control

    Directory of Open Access Journals (Sweden)

    Hasan Fauzi

    2008-06-01

    Full Text Available One important instrument to be used in the control system design is strategic behaviors that can lead to the expected organization performance.  Referring to the extended definition of strategic behavior using stakeholder-based strategic behavior, corporate social performance is kind of strategic behavior to be influenced by using control system. This paper discusses how control system, using Simons‟ levers of control can play important role in increasing the corporate social performance. The interaction between control system, including belief system, boundary system, diagnostic control system, and interactive control system, as well as the corporate financial performance (CFP can affect the corporate social performance (CSP due to fact that increase in CFP resulting from the appropriate use of control system components enables the company has more chance to do the CSP. The levers of control are deemed to form an integral part of employee socialization and support the development of an organization‟s culture, the system of shared beliefs, values, norms, and mores of organizational members which are deemed to be a primary determinant of the direction of employee behavior.

  12. Better Monetary Control may Increase the Inflationary Bias of Policy

    NARCIS (Netherlands)

    O.H. Swank (Otto)

    1994-01-01

    textabstractExplores the implications of imperfect monetary control and uncertainty about the trade-off between output and inflation to discretionary policy. Impact of imperfect control of money growth on policymakers' incentive to create surprises; Consequences of imperfect control of money growth

  13. Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection.

    Science.gov (United States)

    Venkatasubramanian, Sambasivan; Tripathi, Deepak; Tucker, Torry; Paidipally, Padmaja; Cheekatla, Satyanarayana; Welch, Elwyn; Raghunath, Anjana; Jeffers, Ann; Tvinnereim, Amy R; Schechter, Melissa E; Andrade, Bruno B; Mackman, Nizel; Idell, Steven; Vankayalapati, Ramakrishna

    2016-02-01

    Tissue factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TF(Δ) ) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2-like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia.

    Science.gov (United States)

    Rosshandler, Yasmin; Shen, Ann Q; Cortes, Jorge; Khoury, Hanna Jean

    2016-05-01

    Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia.

  15. Development of Plant Control Diagnosis Technology and Increasing Its Applications

    Science.gov (United States)

    Kugemoto, Hidekazu; Yoshimura, Satoshi; Hashizume, Satoru; Kageyama, Takashi; Yamamoto, Toru

    A plant control diagnosis technology was developed to improve the performance of plant-wide control and maintain high productivity of plants. The control performance diagnosis system containing this technology picks out the poor performance loop, analyzes the cause, and outputs the result on the Web page. Meanwhile, the PID tuning tool is used to tune extracted loops from the control performance diagnosis system. It has an advantage of tuning safely without process changes. These systems are powerful tools to do Kaizen (continuous improvement efforts) step by step, coordinating with the operator. This paper describes a practical technique regarding the diagnosis system and its industrial applications.

  16. Detection of an Abnormal Myeloid Clone by Flow Cytometry in Familial Platelet Disorder With Propensity to Myeloid Malignancy.

    Science.gov (United States)

    Ok, Chi Young; Leventaki, Vasiliki; Wang, Sa A; Dinardo, Courtney; Medeiros, L Jeffrey; Konoplev, Sergej

    2016-02-01

    To report aberrant myeloblasts detected by flow cytometry immunophenotypic studies in an asymptomatic patient with familial platelet disorder with propensity to myeloid malignancy, a rare autosomal dominant disease caused by germline heterozygous mutations in Runt-related transcription factor 1. Morphologic evaluation, flow cytometry immunophenotypic studies, nanofluidics-based qualitative multiplex reverse transcriptase polymerase chain reaction, Sanger sequencing, and next-generation sequencing-based mutational hotspot analysis of 53 genes were performed on bone marrow biopsy and aspirate samples. Flow cytometry immunophenotypic analysis showed 0.6% CD34+ blasts with an abnormal immunophenotype: CD13 increased, CD33+, CD38 decreased, CD117 increased, and CD123 increased. The acquisition of new phenotypic aberrancies in myeloblasts as detected by flow cytometry immunophenotypic studies might be a harbinger of impending myelodysplastic syndrome or acute myeloid leukemia in a patient with familial platelet disorder with propensity to myeloid malignancy. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  17. Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms

    International Nuclear Information System (INIS)

    Kobune, M; Iyama, S; Kikuchi, S; Horiguchi, H; Sato, T; Murase, K; Kawano, Y; Takada, K; Ono, K; Kamihara, Y; Hayashi, T; Miyanishi, K; Sato, Y; Takimoto, R; Kato, J

    2012-01-01

    Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34 + cells, CD34 + blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34 + acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO + leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO + leukemic cell proliferation. The demethylating agent, 5-aza-2′-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells

  18. Relative biological effectiveness of tritium for induction of myeloid leukemia in CBA/H mice

    International Nuclear Information System (INIS)

    Johnson, J.R.; Myers, D.K.; Jones, A.R.

    1995-01-01

    To help resolve uncertainties as to the most appropriate weighting factor for tritium β rays, a large experiment was carried out to measure the relative biological effectiveness (RBE) of tritiated water compared to X-rays for the induction of myeloid leukemia in male mice of the CBA/H strain. The study was designed to estimate the lifetime incidence of myeloid leukemia in seven groups of about 750 mice each; radiation exposures were approximately 0, 1, 2 and 3 Gy both for tritiated water and for X rays. The lifetime incidence of leukemia in these mice increased from 0.13% in the control group to 6-8% in groups exposed to higher radiation doses. The results were fitted to various equations relating leukemia incidence to radiation dose, using both the raw data and data corrected for cumulative mouse-days at risk. The calculated RBE values for tritium β rays compared to X rays ranged from 1.0 ± to 1.3 ± 0.3. A w R value or 1 would thus appear to be more appropriate than a w R of 2 tritium β rays. 31 refs., 1 fig., 6 tabs

  19. RBE of tritium for induction of myeloid leukemia in CBA/H mice

    International Nuclear Information System (INIS)

    Myers, D.K.; Jackson, J.S.; Gragtmans, N.J.; Jones, A.R.; Dunford, D.W.; Wyatt, H.M.; Percy, D.H.

    1990-05-01

    In order to help resolve uncertainties as to the most appropriate quality factor for tritium beta rays, a large experiment was carried out to measure the relative biological effectiveness (RBE) of tritiated water compared to X rays for the induction of myeloid leukemia in male mice of CBA/H strain. The study was designed to estimate the lifetime incidence of myeloid leukemia in seven groups of about 750 mice each; radiation exposures were approximately 0, 1, 2 and 3 grays both for tritiated water and X rays. The lifetime incidence of leukemia in these mice increased from 0.13% in the control group to 6-8% in groups exposed to higher radiation doses. The results were fitted to various equations relating leukemia incidence to radiation dose, using both the raw data and data corrected for cumulative animal-days at risk. The calculated RBE values for tritium beta rays compared to X rays ranged from 1.0 ± 0.5 to 1.3 ± 0.3. A best estimate of the RBE for this experiment was about 1.2 ± 0.3. A Q value of 1 would thus appear to be more appropriate than a Q of 2 for tritium beta rays

  20. Relative biological effectiveness of tritium for induction of myeloid leukemia in CBA/H mice

    International Nuclear Information System (INIS)

    Johnson, J.R.; Myers, D.K.; Jackson, J.S.; Dunford, D.W.; Gragtmans, N.J.; Wyatt, H.M.; Jones, A.R.; Percy, D.H.

    1995-01-01

    To help resolve uncertainties as to the most appropriate weighting factor for tritium β rays, a large experiment was carried out to measure the relative biological effectiveness (RBE) of tritiated water compared to X rays for the induction of myeloid leukemia in male mice of the CBA/H strain. The study was designed to estimate the lifetime incidence of myeloid leukemia in seven groups of about 750 mice each; radiation exposures were approximately 0, 1, 2 and 3 Gy both for tritiated water and for X rays. The lifetime incidence of leukemia in these mice increased from 0.13% in the control group to 6-8% in groups exposed to higher radiation doses. The results were fitted to various equations relating leukemia incidence to radiation dose, using both the raw data and data corrected for cumulative mouse-days at risk. The calculated RBE values for tritium 13 rays compared to X rays ranged from 1.0 ± 0.5 to 1.3 ± 0.3. A best estimate of the RBE for this experiment was about 1.2 ± 0.3. A w R value of 1 would thus appear to be more appropriate than a W R of 2 for tritium β rays. (author)

  1. Relative biological effectiveness of tritium for induction of myeloid leukemia in CBA/H mice

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, J.R. [Battelle Pacific Northwest Labs., Health Protection Branch, Health Div., Richland, WA (United States); Myers, D.K.; Jackson, J.S.; Dunford, D.W.; Gragtmans, N.J.; Wyatt, H.M.; Jones, A.R. [Atomic Energy of Canada Limited, Chalk River, Ontairo (Canada); Percy, D.H. [Univ. of Guelph, Ontario Veterinary College, Guelph, Ontario (Canada)

    1995-07-01

    To help resolve uncertainties as to the most appropriate weighting factor for tritium {beta} rays, a large experiment was carried out to measure the relative biological effectiveness (RBE) of tritiated water compared to X rays for the induction of myeloid leukemia in male mice of the CBA/H strain. The study was designed to estimate the lifetime incidence of myeloid leukemia in seven groups of about 750 mice each; radiation exposures were approximately 0, 1, 2 and 3 Gy both for tritiated water and for X rays. The lifetime incidence of leukemia in these mice increased from 0.13% in the control group to 6-8% in groups exposed to higher radiation doses. The results were fitted to various equations relating leukemia incidence to radiation dose, using both the raw data and data corrected for cumulative mouse-days at risk. The calculated RBE values for tritium 13 rays compared to X rays ranged from 1.0 {+-} 0.5 to 1.3 {+-} 0.3. A best estimate of the RBE for this experiment was about 1.2 {+-} 0.3. A w{sub R} value of 1 would thus appear to be more appropriate than a W{sub R} of 2 for tritium {beta} rays. (author)

  2. Relative biological effectiveness of tritium for induction of myeloid leukemia in CBA/H mice.

    Science.gov (United States)

    Johnson, J R; Myers, D K; Jackson, J S; Dunford, D W; Gragtmans, N J; Wyatt, H M; Jones, A R; Percy, D H

    1995-10-01

    To help resolve uncertainties as to the most appropriate weighting factor for tritium beta rays, a large experiment was carried out to measure the relative biological effectiveness (RBE) of tritiated water compared to X rays for the induction of myeloid leukemia in male mice of the CBA/H strain. The study was designed to estimate the lifetime incidence of myeloid leukemia in seven groups of about 750 mice each; radiation exposures were approximately 0, 1, 2 and 3 Gy both for tritiated water and for X rays. The lifetime incidence of leukemia in these mice increased from 0.13% in the control group to 6-8% in groups exposed to higher radiation doses. The results were fitted to various equations relating leukemia incidence to radiation dose, using both the raw data and data corrected for cumulative mouse-days at risk. The calculated RBE values for tritium beta rays compared to X rays ranged from 1.0 +/- 0.5 to 1.3 +/- 0.3. A best estimate of the RBE for this experiment was about 1.2 +/- 0.3. A wR value of 1 would thus appear to be more appropriate than a wR of 2 for tritium beta rays.

  3. Increasing software testability with standard access and control interfaces

    Science.gov (United States)

    Nikora, Allen P; Some, Raphael R.; Tamir, Yuval

    2003-01-01

    We describe an approach to improving the testability of complex software systems with software constructs modeled after the hardware JTAG bus, used to provide visibility and controlability in testing digital circuits.

  4. FcγRIIb on myeloid cells rather than on B cells protects from collagen-induced arthritis.

    Science.gov (United States)

    Yilmaz-Elis, A Seda; Ramirez, Javier Martin; Asmawidjaja, Patrick; van der Kaa, Jos; Mus, Anne-Marie; Brem, Maarten D; Claassens, Jill W C; Breukel, Cor; Brouwers, Conny; Mangsbo, Sara M; Boross, Peter; Lubberts, Erik; Verbeek, J Sjef

    2014-06-15

    Extensive analysis of a variety of arthritis models in germline KO mice has revealed that all four receptors for the Fc part of IgG (FcγR) play a role in the disease process. However, their precise cell type-specific contribution is still unclear. In this study, we analyzed the specific role of the inhibiting FcγRIIb on B lymphocytes (using CD19Cre mice) and in the myeloid cell compartment (using C/EBPαCre mice) in the development of arthritis induced by immunization with either bovine or chicken collagen type II. Despite their comparable anti-mouse collagen autoantibody titers, full FcγRIIb knockout (KO), but not B cell-specific FcγRIIb KO, mice showed a significantly increased incidence and severity of disease compared with wild-type control mice when immunized with bovine collagen. When immunized with chicken collagen, disease incidence was significantly increased in pan-myeloid and full FcγRIIb KO mice, but not in B cell-specific KO mice, whereas disease severity was only significantly increased in full FcγRIIb KO mice compared with incidence and severity in wild-type control mice. We conclude that, although anti-mouse collagen autoantibodies are a prerequisite for the development of collagen-induced arthritis, their presence is insufficient for disease development. FcγRIIb on myeloid effector cells, as a modulator of the threshold for downstream Ab effector pathways, plays a dominant role in the susceptibility to collagen-induced arthritis, whereas FcγRIIb on B cells, as a regulator of Ab production, has a minor effect on disease susceptibility. Copyright © 2014 by The American Association of Immunologists, Inc.

  5. Chemical Weed Control Increases Survival and Growth in Hardwood Plantings

    Science.gov (United States)

    Gayne G. Erdmann

    1967-01-01

    In a plantation of four hardwood species on a silt loam soil planted to 1-0 stock, 4 pounds of active atrazine or simazine controlled weeds effectively without injuring the trees. Chemical weed control was better on plowed and disked ground than on unprepared ground. Yellow-poplar and white ash grew faster on prepared ground. Black walnut and red oak did not respond...

  6. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells

    DEFF Research Database (Denmark)

    Kirstetter, Peggy; Schuster, Mikkel B; Bereshchenko, Oksana

    2008-01-01

    Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p...... penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.......42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete...

  7. Vorinostat in Treating Patients With Acute Myeloid Leukemia

    Science.gov (United States)

    2014-04-30

    Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia; Refractory Cytopenia With Multilineage Dysplasia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  8. 5-Fluoro-2'-Deoxycytidine and Tetrahydrouridine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

    Science.gov (United States)

    2015-06-03

    Adult Acute Myeloid Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  9. Immunodetection of myeloid and plasmacytoid dendritic cells in mammary carcinomas of female dogs

    Directory of Open Access Journals (Sweden)

    Mayara C. Rosolem

    2015-11-01

    Full Text Available ABSTRACT: Dendritic cells have attracted great interest from researchers as they may be used as targets of tumor immune evasion mechanisms. The main objective of this study was to evaluate the relationship between the dendritic cells (DCs subpopulation in simple type mammary carcinomas in female dogs. Two groups of samples were used: the control group consisted of 18 samples of mammary tissue without changes and the tumor group with 26 simple type mammary carcinomas. In these groups, we evaluated the immunodetection of immature and mature myeloid DCs, plasmacytoid DCs and MHC-II. In mammary tumor, mature myeloid DCs predominated in the peritumoral region, while immature myeloid DCs and plasmacytoid DCs were evident in the intratumoral region. Immunostaining of MHC-II was visualized in mammary acini (control group, in tumor cells and inflammatory infiltration associated with tumors. The comparison between the control and tumor groups showed a statistically significant difference between immature myeloid DCs, mature myeloid DCs and plasmacytoid DCs. The immunodetection of MHC-II was not significant when comparing the groups. The predominance of immature DCs in the tumor group is possibly related to an inefficient immune response, promoting the development and survival of tumor cells. The presence of plasmacytoid DCs in the same group suggests a worse prognosis for female dogs with mammary tumors. Therefore, the ability of differentiation of canine dendritic cells could be influenced by neoplastic cells and by the tumor microenvironment.

  10. Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC.

    Directory of Open Access Journals (Sweden)

    Anna Durrans

    Full Text Available Lung cancer is the leading cause of cancer related mortality worldwide, with non-small cell lung cancer (NSCLC as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor "activated/reprogrammed" stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN, chemokine (C-C motif ligand 7 (CCL7 and thrombospondin 1 (TSP1 were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value.

  11. The mitochondrial uniporter controls fight or flight heart rate increases.

    Science.gov (United States)

    Wu, Yuejin; Rasmussen, Tyler P; Koval, Olha M; Joiner, Mei-Ling A; Hall, Duane D; Chen, Biyi; Luczak, Elizabeth D; Wang, Qiongling; Rokita, Adam G; Wehrens, Xander H T; Song, Long-Sheng; Anderson, Mark E

    2015-01-20

    Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates calcium entry into the mitochondrial matrix to stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of a dominant-negative (DN) MCU. Here, we show that DN-MCU mice had normal resting heart rates but were incapable of physiological fight or flight heart rate acceleration. We found that MCU function was essential for rapidly increasing mitochondrial calcium in pacemaker cells and that MCU-enhanced oxidative phoshorylation was required to accelerate reloading of an intracellular calcium compartment before each heartbeat. Our findings show that MCU is necessary for complete physiological heart rate acceleration and suggest that MCU inhibition could reduce inappropriate heart rate increases without affecting resting heart rate.

  12. Cutaneous myeloid sarcoma: natural history and biology of an uncommon manifestation of acute myeloid leukemia.

    Science.gov (United States)

    Hurley, M Yadira; Ghahramani, Grant K; Frisch, Stephanie; Armbrecht, Eric S; Lind, Anne C; Nguyen, Tudung T; Hassan, Anjum; Kreisel, Friederike H; Frater, John L

    2013-05-01

    We conducted a retrospective study of patients with cutaneous myeloid sarcoma, from 2 tertiary care institutions. Eighty-three patients presented, with a mean age of 52 years. Diagnosis of myeloid sarcoma in the skin was difficult due to the low frequency of myeloperoxidase and/or CD34+ cases (56% and 19% of tested cases, respectively). Seventy-one of the 83 patients (86%) had ≥ 1 bone marrow biopsy. Twenty-eight (39%) had acute myeloid leukemia with monocytic differentiation. Twenty-three had other de novo acute myeloid leukemia subtypes. Thirteen patients had other myeloid neoplasms, of which 4 ultimately progressed to an acute myeloid leukemia. Seven had no bone marrow malignancy. Ninety-eight percent of the patients received chemotherapy, and approximately 89% died of causes related to their disease. Cutaneous myeloid sarcoma in most cases represents an aggressive manifestation of acute myeloid leukemia. Diagnosis can be challenging due to lack of myeloblast-associated antigen expression in many cases, and difficulty in distinguishing monocyte-lineage blasts from neoplastic and non-neoplastic mature monocytes.

  13. Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice.

    Science.gov (United States)

    McCullough, Rebecca L; McMullen, Megan R; Das, Dola; Roychowdhury, Sanjoy; Strainic, Michael G; Medof, M Edward; Nagy, Laura E

    2016-07-01

    Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia

    Science.gov (United States)

    Boutzen, Héléna; Saland, Estelle; Larrue, Clément; de Toni, Fabienne; Gales, Lara; Castelli, Florence A.; Cathebas, Mathilde; Zaghdoudi, Sonia; Stuani, Lucille; Kaoma, Tony; Riscal, Romain; Yang, Guangli; Hirsch, Pierre; David, Marion; De Mas-Mansat, Véronique; Delabesse, Eric; Vallar, Laurent; Delhommeau, François; Jouanin, Isabelle; Ouerfelli, Ouathek; Le Cam, Laurent; Linares, Laetitia K.; Junot, Christophe; Portais, Jean-Charles; Vergez, François; Récher, Christian

    2016-01-01

    Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD–Scid–IL2rγnull mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies. PMID:26951332

  15. Monocytic myeloid-derived suppressor cells as prognostic factor in chronic myeloid leukaemia patients treated with dasatinib.

    Science.gov (United States)

    Giallongo, Cesarina; Parrinello, Nunziatina L; La Cava, Piera; Camiolo, Giuseppina; Romano, Alessandra; Scalia, Marina; Stagno, Fabio; Palumbo, Giuseppe A; Avola, Roberto; Li Volti, Giovanni; Tibullo, Daniele; Di Raimondo, Francesco

    2018-02-01

    Myeloid suppressor cells are a heterogeneous group of myeloid cells that are increased in patients with chronic myeloid leukaemia (CML) inducing T cell tolerance. In this study, we found that therapy with tyrosine kinase inhibitors (TKI) decreased the percentage of granulocytic MDSC, but only patients treated with dasatinib showed a significant reduction in the monocytic subset (M-MDSC). Moreover, a positive correlation was observed between number of persistent M-MDSC and the value of major molecular response in dasatinib-treated patients. Serum and exosomes from patients with CML induced conversion of monocytes from healthy volunteers into immunosuppressive M-MDSC, suggesting a bidirectional crosstalk between CML cells and MDSC. Overall, we identified M-MDSC as prognostic factors in patients treated with dasatinib. It might be of interest to understand whether MDSC may be a candidate predictive markers of relapse risk following TKI discontinuation, suggesting their potential significance as practice of precision medicine. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  16. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Kazuya Takahashi

    2007-04-01

    Full Text Available BACKGROUND: In multiple sclerosis, inflammation can successfully be prevented, while promoting repair is still a major challenge. Microglial cells, the resident phagocytes of the central nervous system (CNS, are hematopoietic-derived myeloid cells and express the triggering receptor expressed on myeloid cells 2 (TREM2, an innate immune receptor. Myeloid cells are an accessible source for ex vivo gene therapy. We investigated whether myeloid precursor cells genetically modified to express TREM2 affect the disease course of experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis. METHODS AND FINDINGS: EAE was induced in mice by immunization with a myelin autoantigen. Intravenous application of TREM2-transduced bone marrow-derived myeloid precursor cells at the EAE peak led to an amelioration of clinical symptoms, reduction in axonal damage, and prevention of further demyelination. TREM2-transduced myeloid cells applied intravenously migrated into the inflammatory spinal cord lesions of EAE-diseased mice, showed increased lysosomal and phagocytic activity, cleared degenerated myelin, and created an anti-inflammatory cytokine milieu within the CNS. CONCLUSIONS: Intravenously applied bone marrow-derived and TREM2-tranduced myeloid precursor cells limit tissue destruction and facilitate repair within the murine CNS by clearance of cellular debris during EAE. TREM2 is a new attractive target for promotion of repair and resolution of inflammation in multiple sclerosis and other neuroinflammatory diseases.

  17. Modifying factors of radiation induced myeloid leukemia of C3H/He mouse

    International Nuclear Information System (INIS)

    Yoshida, Kazuko; Nishimura, Mayumi; Nemoto, Kumie; Seki, Masatoshi

    1989-01-01

    The first experiment examined modifying factors, such as adrenocortical hormones, inflammatory reaction, and surgical stress, for radiation induced myeloid leukemia in C3H/He mice. The incidence of myeloid leukemia was not affected by a solitary subcutaneous injection of one mg of prednisolone acetate (predonine), but increased significantly by whole body irradiation, immediately followed by predonine. Augumentated effects of predonine was found in the 0.47 Gy, 1.42 Gy, and 2.84 Gy irradiated groups, but not found in the 4.73 Gy irradiated group. These results suggest that predonine itself did not have any effect on initiation of leukemogenesis, but promoted the incidence of radiation-induced myeloid leukemia. In the next experiment determining whether the incidence of myeloid leukemia was increased with stimulation of hematopoietic tissues, mice were inserted a piece of cellulose acetate membrane (CAM) into the peritoneal cavity. In the non-irradiated group of mice, CAM insertion did not affect the incidence of myeloid leukemia at all. The incidence of leukemia increased significantly by CAM insertion combined with irradiation of 2.84 Gy. Mice suffered from both surgical stress and inflammatory reaction after CAM insertion. Therefore, surgical stress was considered responsible for the development of radiation-induced leukemia. (Namekawa, K)

  18. PDGFRα promoter polymorphisms and expression patterns influence risk of development of imatinib-induced thrombocytopenia in chronic myeloid leukemia: A study from India.

    Science.gov (United States)

    Guru, Sameer Ahmad; Mir, Rashid; Bhat, Musadiq; Najar, Imtiyaz; Zuberi, Mariyam; Sumi, Mamta; Masroor, Mirza; Gupta, Naresh; Saxena, Alpana

    2017-10-01

    myeloid leukemia patient groups (p chronic myeloid leukemia patients were associated with an increased risk of developing thrombocytopenia, with odds ratios 6.5 (95% confidence interval = 2.02-0.89, p = 0.001) and 6.0 (95% confidence interval = 2.26-15.91, p = 0.0002), respectively. Similarly, -909C/A promoter polymorphism genotype distribution also differed significantly between thrombocytopenic and non-thrombocytopenic chronic myeloid leukemia patient groups (p = 0.02), and a significantly increased risk of imatinib-induced thrombocytopenia was associated with -909C/A polymorphism mutant homozygous (AA) genotypes the odds ratio being 7.7 (95% confidence interval 1.50 to 39.91, p = 0.009). However, no significant risk of imatinib-induced thrombocytopenia was found to be associated with heterozygous genotype (-909C/A) with odds ratio 1.9 (95% confidence interval = 0.86-4.56, p = 1.14). Platelet-derived growth factor receptor-α messenger RNA expression was significantly higher in chronic myeloid leukemia patients compared to controls (p = 0.008). Moreover, patients with imatinib-induced thrombocytopenia had a significantly lower platelet-derived growth factor receptor-α messenger RNA expression, compared to patients without thrombocytopenia (p = 0.01). A differential expression of platelet-derived growth factor receptor-α messenger RNA was observed with respect to different +68 GA ins/del and -909C/A polymorphism genotypes. The +68GA deletion allele and -909A allele were significantly associated with lower expression of platelet-derived growth factor receptor-α messenger RNA. The platelet-derived growth factor receptor-α +68GA del/del, +68GA ins/del, and -909AA genotypes are associated with an increased risk of developing thrombocytopenia in imatinib-treated chronic myeloid leukemia patients. A significantly lower platelet-derived growth factor receptor-α messenger RNA expression accompanies the +68GA deletion allele in an

  19. Plenty of frauds. Increase of delinquency or better customs controls?

    International Nuclear Information System (INIS)

    D'Erceville, H.

    1997-01-01

    In 1995, the French taxation authorities have identified 1849 violations of law concerning the petroleum products, which correspond to a 53% increase with respect to 1994. The discovery of these frauds has permitted the recovery of 85 millions of French Francs (MFF) of taxes and rights, from which 61.1 MFF correspond to the internal tax on petroleum products (TIPP). In France, the TIPP represents 65% of the customs receipts and about 10% of the gross fiscal receipt of the general budget of the nation. Such delinquency actions can exist at any step of the petroleum file from the production to the storage of petroleum products. (J.S.)

  20. Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Patient Version

    Science.gov (United States)

    Childhood acute myeloid leukemia and other myeloid malignancies treatment may include chemotherapy, radiation therapy, stem cell transplant, and targeted therapy. Learn more about AML and myelodysplastic/myeloproliferative diseases in this expert-reviewed summary.

  1. Genetics Home Reference: cytogenetically normal acute myeloid leukemia

    Science.gov (United States)

    ... Testing (1 link) Genetic Testing Registry: Acute myeloid leukemia Other Diagnosis and Management Resources (3 links) Fred Hutchinson Cancer Research Center National Cancer Institute: Acute Myeloid Leukemia Treatment St. Jude Children's Research Hospital General Information ...

  2. Do We Know What Causes Chronic Myeloid Leukemia?

    Science.gov (United States)

    ... Be Prevented? More In Chronic Myeloid Leukemia About Chronic Myeloid Leukemia Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treatment After Treatment Back To Top Imagine a world ...

  3. Increasing flexibility of coal power plant by control system modifications

    Directory of Open Access Journals (Sweden)

    Marušić Ante

    2016-01-01

    Full Text Available Expanding implementation of intermittent renewable energy sources has already started to change the role of thermal power plants in energy systems across Europe. Traditionally base load plants are now forced to operate as peaking plants. A familiar transition in upcoming years is expected in Croatia and coal power plant operators are preparing accordingly. To evaluate cycling capabilities and control system operation for flexible operation of selected 210 MW coal plant, series of tests with different load gradients were performed and results were thoroughly analyzed. Two possible “bottlenecks” are identified, thermal stress in superheater header, and achievable ramping rate considering operational limitations of coal feeders, firing system and evaporator dynamics. Several unexpected readings were observed, usually caused by malfunctioning sensors and equipment, resulting in unexpected oscillations of superheated steam temperature. Based on superheater geometry and experimental data, maximal steam temperature gradient during ramping was evaluated. Since thermal stress was well inside the safety margins, the simulation model of the whole boiler was used to evaluate achievable ramping on electric side.

  4. Diagnosis of chronic myeloid leukemia

    International Nuclear Information System (INIS)

    Demitrovicova, L.; Mikuskova, E.; Copakova, L.; Leitnerova, M.

    2012-01-01

    Chronic myeloid leukemia (CML) was the first cancer associated with the specific chromosomal aberration. Philadelphia chromosome due to translocation (9, 22) is present in 95% cases, fusion gene BCR/ABL is present in 100% cases at the time of diagnosis. Disease has its own characteristics detectable by physical examination, by the examination of blood count and differential and by cytomorhologic examination of bone marrow, however the diagnosis of CML is determined by cytogenetics and molecular genetics. If the diagnosis of Ph+ BCR/ABL positive CML is confirmed, the disease is treated by tyrosine kinase inhibitors (TKI). TKI don´t affect formation of leukemic gene BCR/ABL, but they can stop the action of this gene. The target therapy of tyrosine kinase inhibitors markedly improved the survival of patients with CML by inhibition the proliferation of leukemic clone on the clinically safety level of minimal disease, although probably this treatment cannot cure the CML. Cytogenetics and molecular genetics are very important at the monitoring of residual disease with sensitivity 10"-"6. (author)

  5. Comorbidity and performance status in acute myeloid leukemia patients

    DEFF Research Database (Denmark)

    Ostgård, L S G; Nørgaard, J M; Sengeløv, H

    2015-01-01

    As the world population ages, the comorbidity burden in acute myeloid leukemia (AML) patients increases. Evidence on how to integrate comorbidity measures into clinical decision-making is sparse. We determined the prognostic impact of comorbidity and World Health Organization Performance Status (PS...... with an increased short- and long-term mortality (adjusted 90 day MR, PS⩾2=3.43 (95%CI=2.30-5.13); adjusted 91 day-3 year MR=1.35 (95%CI=1.06-1.74)). We propose that more patients with comorbidity may benefit from intensive chemotherapy.Leukemia advance online publication, 2 September 2014; doi:10.1038/leu.2014.234....

  6. The Epigenetic Landscape of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Emma Conway O’Brien

    2014-01-01

    Full Text Available Acute myeloid leukemia (AML is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.

  7. Differentiation Therapy of Acute Myeloid Leukemia

    International Nuclear Information System (INIS)

    Gocek, Elzbieta; Marcinkowska, Ewa

    2011-01-01

    Acute Myeloid Leukemia (AML) is a predominant acute leukemia among adults, characterized by accumulation of malignantly transformed immature myeloid precursors. A very attractive way to treat myeloid leukemia, which is now called ‘differentiation therapy’, was proposed as in vitro studies have shown that a variety of agents stimulate differentiation of the cell lines isolated from leukemic patients. One of the differentiation-inducing agents, all-trans retinoic acid (ATRA), which can induce granulocytic differentiation in myeloid leukemic cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a t(15;17)(q22;q12) chromosomal translocation. Because differentiation therapy using ATRA has significantly improved prognosis for patients with APL, many efforts have been made to find alternative differentiating agents. Since 1,25-dihydroxyvitamin D 3 (1,25D) is capable of inducing in vitro monocyte/macrophage differentiation of myeloid leukemic cells, clinical trials have been performed to estimate its potential to treat patients with AML or myelodysplastic syndrome (MDS). Unfortunately therapeutic concentrations of 1,25D can induce potentially fatal systemic hypercalcemia, thus limiting clinical utility of that compound. Attempts to overcome this problem have focused on the synthesis of 1,25D analogs (VDAs) which retain differentiation inducing potential, but lack its hypercalcemic effects. This review aims to discuss current problems and potential solutions in differentiation therapy of AML

  8. Differentiation Therapy of Acute Myeloid Leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Gocek, Elzbieta; Marcinkowska, Ewa, E-mail: ema@cs.uni.wroc.pl [Department of Biotechnology, University of Wroclaw, ul Tamka 2, Wroclaw 50-137 (Poland)

    2011-05-16

    Acute Myeloid Leukemia (AML) is a predominant acute leukemia among adults, characterized by accumulation of malignantly transformed immature myeloid precursors. A very attractive way to treat myeloid leukemia, which is now called ‘differentiation therapy’, was proposed as in vitro studies have shown that a variety of agents stimulate differentiation of the cell lines isolated from leukemic patients. One of the differentiation-inducing agents, all-trans retinoic acid (ATRA), which can induce granulocytic differentiation in myeloid leukemic cell lines, has been introduced into clinics to treat patients with acute promyelocytic leukemia (APL) in which a PML-RARA fusion protein is generated by a t(15;17)(q22;q12) chromosomal translocation. Because differentiation therapy using ATRA has significantly improved prognosis for patients with APL, many efforts have been made to find alternative differentiating agents. Since 1,25-dihydroxyvitamin D{sub 3} (1,25D) is capable of inducing in vitro monocyte/macrophage differentiation of myeloid leukemic cells, clinical trials have been performed to estimate its potential to treat patients with AML or myelodysplastic syndrome (MDS). Unfortunately therapeutic concentrations of 1,25D can induce potentially fatal systemic hypercalcemia, thus limiting clinical utility of that compound. Attempts to overcome this problem have focused on the synthesis of 1,25D analogs (VDAs) which retain differentiation inducing potential, but lack its hypercalcemic effects. This review aims to discuss current problems and potential solutions in differentiation therapy of AML.

  9. Effect of daily low dose gamma irradiation on growth and differentiation of human myeloid leukaemic bone marrow in diffusion chambers

    Energy Technology Data Exchange (ETDEWEB)

    Greenberger, J S [Joint Center for Radiation Therapy, Department of Radiation and Sidney Farber Cancer Institute; Chang, J M; King, V; Fulmer, S; Balzuno, S; Moloney, W C [Division of Hematology, Department of Medicine, Brigham and Women' s Hospital Harvard Medical School, Boston, USA

    1981-01-01

    Bone marrow from each of 8 untreated patients with myeloproliferative disorders was grown in diffusion chambers in 760 rad total body irradiated rats. Rats were exposed to 11.5, 57.5, or 108.5 rad daily for 14-21 and cell growth compared to that detected in unirradiated chambers. Cells from acute myelogenous leukaemia patients exposed to 11.5 rad per d grew for 11-21 d and there was no consistent stimulation of differentiation of immature granulocytic cells to mature granulocytes that was attributable to irradiation. Cells from a chronic myeloid leukaemia patient in chronic phase or blast crisis, and a polycythaemia vera patient with myeloid metaplasia showed signigicant morphologic differentiation from immature to mature granulocytes in control chambers with no additional effect of daily irradiation. Marrow specimens from 2 AML patients exposed to each of 3 daily dose fractions over 14 d revealed a dose-dependent decrease in immature granulocytes with no persistent increase in mature granulocytes. In both irradiated and control chambers, macrophages increased over 21 d. Thus, cells from patients with myeloprofilerative disorders may not necessarily differentiate to mature granulocytes following in vivo exposure to ionizing irradiation.

  10. AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia

    Science.gov (United States)

    2018-03-12

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  11. Extramedullary leukemia in children with acute myeloid leukemia

    DEFF Research Database (Denmark)

    Støve, Heidi Kristine; Sandahl, Julie Damgaard; Abrahamsson, Jonas

    2017-01-01

    BACKGROUND: The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified. PROCEDURE: This population-based study included 315 children from the NOPHO-AML 2004 trial. RESULTS: At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma...... the OS. No patients relapsed at the primary site of the myeloid sarcoma despite management without radiotherapy....

  12. Genetics Home Reference: familial acute myeloid leukemia with mutated CEBPA

    Science.gov (United States)

    ... Familial acute myeloid leukemia with mutated CEBPA Familial acute myeloid leukemia with mutated CEBPA Printable PDF Open All Close ... on PubMed (1 link) PubMed OMIM (1 link) LEUKEMIA, ACUTE MYELOID Sources for This Page Carmichael CL, Wilkins EJ, ...

  13. Genetics Home Reference: core binding factor acute myeloid leukemia

    Science.gov (United States)

    ... binding factor acute myeloid leukemia Core binding factor acute myeloid leukemia Printable PDF Open All Close All Enable Javascript ... on PubMed (1 link) PubMed OMIM (1 link) LEUKEMIA, ACUTE MYELOID Sources for This Page Goyama S, Mulloy JC. Molecular ...

  14. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

    Science.gov (United States)

    Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

    2016-07-01

    Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. © 2016 John Wiley & Sons A/S.

  15. Donor-Derived Myeloid Sarcoma in Two Kidney Transplant Recipients from a Single Donor

    Directory of Open Access Journals (Sweden)

    Amudha Palanisamy

    2015-01-01

    Full Text Available We report the rare occurrence of donor-derived myeloid sarcoma in two kidney transplant patients who received organs from a single deceased donor. There was no evidence of preexisting hematologic malignancy in the donor at the time of organ recovery. Both recipients developed leukemic involvement that appeared to be limited to the transplanted organ. Fluorescence in situ hybridization (FISH and molecular genotyping analyses confirmed that the malignant cells were of donor origin in each patient. Allograft nephrectomy and immediate withdrawal of immunosuppression were performed in both cases; systemic chemotherapy was subsequently administered to one patient. Both recipients were in remission at least one year following the diagnosis of donor-derived myeloid sarcoma. These cases suggest that restoration of the immune system after withdrawal of immunosuppressive therapy and allograft nephrectomy may be sufficient to control HLA-mismatched donor-derived myeloid sarcoma without systemic involvement.

  16. Excess circulating alternatively activated myeloid (M2 cells accelerate ALS progression while inhibiting experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Ilan Vaknin

    Full Text Available Circulating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs, representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease.We tested this working hypothesis in amyotrophic lateral sclerosis (ALS and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2 cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1 mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE, which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS, revealed a two-fold increase in the percentage of circulating MDSCs (LIN(-/LowHLA-DR(-CD33(+ compared to controls.Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might

  17. History of myeloid-derived suppressor cells.

    Science.gov (United States)

    Talmadge, James E; Gabrilovich, Dmitry I

    2013-10-01

    Tumour-induced granulocytic hyperplasia is associated with tumour vasculogenesis and escape from immunity via T cell suppression. Initially, these myeloid cells were identified as granulocytes or monocytes; however, recent studies have revealed that this hyperplasia is associated with populations of multipotent progenitor cells that have been identified as myeloid-derived suppressor cells (MDSCs). The study of MDSCs has provided a wealth of information regarding tumour pathobiology, has extended our understanding of neoplastic progression and has modified our approaches to immune adjuvant therapy. In this Timeline article, we discuss the history of MDSCs, their influence on tumour progression and metastasis, and the crosstalk between tumour cells, MDSCs and the host macroenvironment.

  18. Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration

    DEFF Research Database (Denmark)

    Ohki, Makiko; Ohki, Yuichi; Ishihara, Makoto

    2010-01-01

    tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool......-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b(+) cells and VEGFR-1(+) cells, but not carrier-mobilized cells or CD11b(-) cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb...... and mobilizes CD45(+)CD11b(+) proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPA improves the incorporation of CD11b(+) cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF...

  19. Daunorubicin Hydrochloride, Cytarabine and Oblimersen Sodium in Treating Patients With Previously Untreated Acute Myeloid Leukemia

    Science.gov (United States)

    2013-06-04

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  20. An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells.

    Science.gov (United States)

    Zaidi, Sayyed K; Perez, Andrew W; White, Elizabeth S; Lian, Jane B; Stein, Janet L; Stein, Gary S

    2017-06-20

    Acute myeloid leukemia (AML) is characterized by an aggressive clinical course and frequent cytogenetic abnormalities that include specific chromosomal translocations. The 8;21 chromosomal rearrangement disrupts the key hematopoietic RUNX1 transcription factor, and contributes to leukemia through recruitment of co-repressor complexes to RUNX1 target genes, altered subnuclear localization, and deregulation of the myeloid gene regulatory program. However, a role of non-coding microRNAs (miRs) in t(8;21)-mediated leukemogenesis is minimally understood. We present evidence of an interplay between the tumor suppressor miR-29b-1 and the AML1-ETO (also designated RUNX1-RUNX1T1) oncogene that is encoded by the t(8;21). We find that AML1-ETO and corepressor NCoR co-occupy the miR-29a/b-1 locus and downregulate its expression in leukemia cells. Conversely, re-introduction of miR-29b-1 in leukemia cells expressing AML1-ETO causes significant downregulation at the protein level through direct targeting of the 3' untranslated region of the chimeric transcript. Restoration of miR-29b-1 expression in leukemia cells results in decreased cell growth and increased apoptosis. The AML1-ETO-dependent differentiation block and transcriptional program are partially reversed by miR-29b-1. Our findings establish a novel regulatory circuit between the tumor-suppressive miR-29b-1 and the oncogenic AML1-ETO that controls the leukemic phenotype in t(8;21)-carrying acute myeloid leukemia.

  1. Tyrosine Kinase Inhibitor Treatment for Newly Diagnosed Chronic Myeloid Leukemia.

    Science.gov (United States)

    Radich, Jerald P; Mauro, Michael J

    2017-08-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder that accounts for approximately 10% of new cases of leukemia. The introduction of tyrosine kinase inhibitors has led to a reduction in mortalities. Thus, the estimated prevalence of CML is increasing. The National Comprehensive Cancer Network and the European Leukemia Net guidelines incorporate frequent molecular monitoring of the fusion BCR-ABL transcript to ensure that patients reach and keep treatment milestones. Most patients with CML are diagnosed in the chronic phase, and approximately 10% to 30% of these patients will at some time in their course meet definition criteria of resistance to imatinib. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Control of proliferating potential of myeloid leukemia cells during long-term treatment with vitamin D3 analogues and other differentiation inducers in combination with antileukemic drugs: in vitro and in vivo studies.

    Science.gov (United States)

    Kasukabe, T; Honma, Y; Hozumi, M; Suda, T; Nishii, Y

    1987-01-15

    Growth inhibition of murine and human myeloid leukemia cells by differentiation inducers during long-term culture was examined to improve the strategy for therapy of myeloid leukemia by differentiation inducers. When the effect of 1 alpha,25-dihydroxyvitamin D3, a typical differentiation inducer, on proliferation of mouse myeloid leukemia M1 cells was examined at a constant product of time and concentration (480 nM in 20 days), the continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3 was the most effective for inhibition of cell proliferation. After 20 days, the cumulative cell number was reduced about 3 X 10(5) times by continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3. Similar results were obtained when M1 cells were treated continuously with dexamethasone. M1 cells resistant to 1 alpha,25-dihydroxyvitamin D3 appeared about 25 days after the start of continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3. On the other hand, when M1 cells were treated continuously with 1 alpha,25-dihydroxyvitamin D3 and noncytotoxic doses of antileukemic drugs such as 1-beta-D-arabinofuranosylcytosine and daunomycin, resistant cells did not appear for at least 35 days. A similar effect of 1 alpha,25-dihydroxyvitamin D3 and antileukemic drugs on cell proliferation was observed with the human monoblast-like cell line U937. The survival of syngeneic SL mice inoculated with M1 cells was prolonged more by treatment with both 1 alpha-hydroxyvitamin D3 and daunomycin than by treatment with either drug alone. These results suggest that continuous treatment with both differentiation inducers and certain antileukemic drugs may be more effective therapeutically than treatment with a differentiation inducer alone.

  3. Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR⁻/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma

    DEFF Research Database (Denmark)

    Brimnes, M K; Vangsted, Annette Juul; Knudsen, L M

    2010-01-01

    Patients with multiple myeloma (MM) suffer from a general impaired immunity comprising deficiencies in humoral responses, T-cell responses as well as dendritic cell (DC) function. Thus, to achieve control of tumour growth through immune therapy constitutes a challenge. Careful evaluation of the i......Patients with multiple myeloma (MM) suffer from a general impaired immunity comprising deficiencies in humoral responses, T-cell responses as well as dendritic cell (DC) function. Thus, to achieve control of tumour growth through immune therapy constitutes a challenge. Careful evaluation...

  4. Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR⁻/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma

    DEFF Research Database (Denmark)

    Brimnes, Marie Klinge; Vangsted, Annette Juul; Meldgaard Knudsen, Lene

    2010-01-01

    +FOXP3+ Treg cells was increased in patients at diagnosis and not in patients in remission or with MGUS. Also, Treg cells from patients with MM were functionally intact as they were able to inhibit proliferation of both CD4 and CD8 T cells. Finally, we observed an increase in the proportion of CD14+HLA-DR...... as a consequence of the disease....

  5. Myeloid malignancies: mutations, models and management

    International Nuclear Information System (INIS)

    Murati, Anne; Brecqueville, Mandy; Devillier, Raynier; Mozziconacci, Marie-Joelle; Gelsi-Boyer, Véronique; Birnbaum, Daniel

    2012-01-01

    Myeloid malignant diseases comprise chronic (including myelodysplastic syndromes, myeloproliferative neoplasms and chronic myelomonocytic leukemia) and acute (acute myeloid leukemia) stages. They are clonal diseases arising in hematopoietic stem or progenitor cells. Mutations responsible for these diseases occur in several genes whose encoded proteins belong principally to five classes: signaling pathways proteins (e.g. CBL, FLT3, JAK2, RAS), transcription factors (e.g. CEBPA, ETV6, RUNX1), epigenetic regulators (e.g. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), tumor suppressors (e.g. TP53), and components of the spliceosome (e.g. SF3B1, SRSF2). Large-scale sequencing efforts will soon lead to the establishment of a comprehensive repertoire of these mutations, allowing for a better definition and classification of myeloid malignancies, the identification of new prognostic markers and therapeutic targets, and the development of novel therapies. Given the importance of epigenetic deregulation in myeloid diseases, the use of drugs targeting epigenetic regulators appears as a most promising therapeutic approach

  6. Leishmania Hijacks Myeloid Cells for Immune Escape

    Directory of Open Access Journals (Sweden)

    María Martínez-López

    2018-05-01

    Full Text Available Protozoan parasites of the Leishmania genus are the causative agents of leishmaniasis, a group of neglected tropical diseases whose clinical manifestations vary depending on the infectious Leishmania species but also on host factors. Recognition of the parasite by host myeloid immune cells is a key to trigger an effective Leishmania-specific immunity. However, the parasite is able to persist in host myeloid cells by evading, delaying and manipulating host immunity in order to escape host resistance and ensure its transmission. Neutrophils are first in infiltrating infection sites and could act either favoring or protecting against infection, depending on factors such as the genetic background of the host or the parasite species. Macrophages are the main host cells where the parasites grow and divide. However, macrophages are also the main effector population involved in parasite clearance. Parasite elimination by macrophages requires the priming and development of an effector Th1 adaptive immunity driven by specific subtypes of dendritic cells. Herein, we will provide a comprehensive outline of how myeloid cells regulate innate and adaptive immunity against Leishmania, and the mechanisms used by the parasites to promote their evasion and sabotage. Understanding the interactions between Leishmania and the host myeloid cells may lead to the development of new therapeutic approaches and improved vaccination to leishmaniases, an important worldwide health problem in which current therapeutic or preventive approaches are limited.

  7. Rho GTPase expression in human myeloid cells.

    Directory of Open Access Journals (Sweden)

    Suzanne F G van Helden

    Full Text Available Myeloid cells are critical for innate immunity and the initiation of adaptive immunity. Strict regulation of the adhesive and migratory behavior is essential for proper functioning of these cells. Rho GTPases are important regulators of adhesion and migration; however, it is unknown which Rho GTPases are expressed in different myeloid cells. Here, we use a qPCR-based approach to investigate Rho GTPase expression in myeloid cells.We found that the mRNAs encoding Cdc42, RhoQ, Rac1, Rac2, RhoA and RhoC are the most abundant. In addition, RhoG, RhoB, RhoF and RhoV are expressed at low levels or only in specific cell types. More differentiated cells along the monocyte-lineage display lower levels of Cdc42 and RhoV, while RhoC mRNA is more abundant. In addition, the Rho GTPase expression profile changes during dendritic cell maturation with Rac1 being upregulated and Rac2 downregulated. Finally, GM-CSF stimulation, during macrophage and osteoclast differentiation, leads to high expression of Rac2, while M-CSF induces high levels of RhoA, showing that these cytokines induce a distinct pattern. Our data uncover cell type specific modulation of the Rho GTPase expression profile in hematopoietic stem cells and in more differentiated cells of the myeloid lineage.

  8. Luteoloside Inhibits Proliferation of Human Chronic Myeloid ...

    African Journals Online (AJOL)

    Purpose: To investigate the effects of luteoloside on the proliferation of human chronic myeloid leukemia K562 cells and whether luteoloside induces cell cycle arrest and apoptosis in K562 cells. Methods: Luteoloside's cytotoxicity was assessed using a cell counting kit. Cell cycle distribution was analysed by flow cytometry ...

  9. Chronic myeloid leukemia: reminiscences and dreams

    Science.gov (United States)

    Mughal, Tariq I.; Radich, Jerald P.; Deininger, Michael W.; Apperley, Jane F.; Hughes, Timothy P.; Harrison, Christine J.; Gambacorti-Passerini, Carlo; Saglio, Giuseppe; Cortes, Jorge; Daley, George Q.

    2016-01-01

    With the deaths of Janet Rowley and John Goldman in December 2013, the world lost two pioneers in the field of chronic myeloid leukemia. In 1973, Janet Rowley, unraveled the cytogenetic anatomy of the Philadelphia chromosome, which subsequently led to the identification of the BCR-ABL1 fusion gene and its principal pathogenetic role in the development of chronic myeloid leukemia. This work was also of major importance to support the idea that cytogenetic changes were drivers of leukemogenesis. John Goldman originally made seminal contributions to the use of autologous and allogeneic stem cell transplantation from the late 1970s onwards. Then, in collaboration with Brian Druker, he led efforts to develop ABL1 tyrosine kinase inhibitors for the treatment of patients with chronic myeloid leukemia in the late 1990s. He also led the global efforts to develop and harmonize methodology for molecular monitoring, and was an indefatigable organizer of international conferences. These conferences brought together clinicians and scientists, and accelerated the adoption of new therapies. The abundance of praise, tributes and testimonies expressed by many serve to illustrate the indelible impressions these two passionate and affable scholars made on so many people’s lives. This tribute provides an outline of the remarkable story of chronic myeloid leukemia, and in writing it, it is clear that the historical triumph of biomedical science over this leukemia cannot be considered without appreciating the work of both Janet Rowley and John Goldman. PMID:27132280

  10. Bcl-2 Protein Expression in Egyptian Acute Myeloid Leukemia

    International Nuclear Information System (INIS)

    El-Shakankiry, N.; El-Sayed, Gh.M.M.; El-Maghraby, Sh.; Moneer, M.M.

    2009-01-01

    Objective: The primary cause of treatment failure in acute myeloid leukemia (AML) is the emergence of both resistant disease and early relapse. The bcl-2 gene encodes a 26-kDa protein that promotes cell survival by blocking programmed cell death (apoptosis). In the present study, bcl-2 protein expression was evaluated in newly diagnosed AML patients and correlated with the induction of remission and overall survival (OS), in an attempt to define patients who might benefit from modified therapeutic strategies. Patients and methods: Pretreatment cellular bcl-2 protein expression was measured in bone marrow samples obtained from 68 patients of newly diagnosed acute myeloid leukemia and 10 healthy controls by western blotting. Results: The mean bcl-2 protein expression was significantly higher in patients (0.68610.592) compared to controls (0.313±0.016) (p=0.002). The overall survival for patients with mean bcl-2 expression of less, and more than or equal to 0.315, was 67% and 56%, respectively, with no significant difference between the two groups 0»=0.86). Conclusion: Even though we did not observe a significant difference in overall survival between patients with high and low levels of bcl-2, modulation of this protein might still be considered as an option for enhancing the effectiveness of conventional chemotherapy.

  11. Myeloid-derived suppressor cells in breast cancer.

    Science.gov (United States)

    Markowitz, Joseph; Wesolowski, Robert; Papenfuss, Tracey; Brooks, Taylor R; Carson, William E

    2013-07-01

    Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their suppressive actions on immune cells such as T cells, dendritic cells, and natural killer cells. MDSCs typically are positive for the markers CD33 and CD11b but express low levels of HLADR in humans. In mice, MDSCs are typically positive for both CD11b and Gr1. These cells exert their suppressive activity on the immune system via the production of reactive oxygen species, arginase, and cytokines. These factors subsequently inhibit the activity of multiple protein targets such as the T cell receptor, STAT1, and indoleamine-pyrrole 2,3-dioxygenase. The numbers of MDSCs tend to increase with cancer burden while inhibiting MDSCs improves disease outcome in murine models. MDSCs also inhibit immune cancer therapeutics. In light of the poor prognosis of metastatic breast cancer in women and the correlation of increasing levels of MDSCs with increasing disease burden, the purposes of this review are to (1) discuss why MDSCs may be important in breast cancer, (2) describe model systems used to study MDSCs in vitro and in vivo, (3) discuss mechanisms involved in MDSC induction/function in breast cancer, and (4) present pre-clinical and clinical studies that explore modulation of the MDSC-immune system interaction in breast cancer. MDSCs inhibit the host immune response in breast cancer patients and diminishing MDSC actions may improve therapeutic outcomes.

  12. Deletion of Rac1GTPase in the Myeloid Lineage Protects against Inflammation-Mediated Kidney Injury in Mice.

    Directory of Open Access Journals (Sweden)

    Miki Nagase

    Full Text Available Macrophage-mediated inflammation has been implicated in various kidney diseases. We previously reported that Rac1, a Rho family small GTP-binding protein, was overactivated in several chronic kidney disease models, and that Rac1 inhibitors ameliorated renal injury, in part via inhibition of inflammation, but the detailed mechanisms have not been clarified. In the present study, we examined whether Rac1 in macrophages effects cytokine production and the inflammatory mechanisms contributing to kidney derangement. Myeloid-selective Rac1 flox control (M-Rac1 FC and knockout (M-Rac1 KO mice were generated using the cre-loxP system. Renal function under basal conditions did not differ between M-Rac1 FC and KO mice. Accordingly, lipopolysaccharide (LPS-evoked kidney injury model was created. LPS elevated blood urea nitrogen and serum creatinine, enhanced expressions of kidney injury biomarkers, Kim-1 and Ngal, and promoted tubular injury in M-Rac1 FC mice. By contrast, deletion of myeloid Rac1 almost completely prevented the LPS-mediated renal impairment. LPS triggered a marked induction of macrophage-derived inflammatory cytokines, IL-6 and TNFα, in M-Rac1 FC mice, which was accompanied by Rac1 activation, stimulation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH oxidase, and reactive oxygen species overproduction. These changes were inhibited in M-Rac1 KO mice. LPS evoked F4/80-positive macrophages accumulation in the kidney, which was not affected by myeloid Rac1 deficiency. We further tested the role of Rac1 signaling in cytokine production using macrophage cell line, RAW264.7. Exposure to LPS increased IL-6 and TNFα mRNA expression. The LPS-driven cytokine induction was dose-dependently blocked by the Rac1 inhibitor EHT1864, NADPH oxidase inhibitor diphenyleneiodonium, and NF-κB inhibitor BAY11-7082. In conclusion, genetic ablation of Rac1 in the myeloid lineage protected against LPS-induced renal inflammation and injury, by

  13. Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers

    Science.gov (United States)

    Rushton, L; Schnatter, A R; Tang, G; Glass, D C

    2014-01-01

    Background: High benzene exposure causes acute myeloid leukaemia (AML). Three petroleum case–control studies identified 60 cases (241 matched controls) for AML and 80 cases (345 matched controls) for chronic lymphoid leukaemia (CLL). Methods: Cases were classified and scored regarding uncertainty by two haematologists using available diagnostic information. Blinded quantitative benzene exposure assessment used work histories and exposure measurements adjusted for era-specific circumstances. Statistical analyses included conditional logistic regression and penalised smoothing splines. Results: Benzene exposures were much lower than previous studies. Categorical analyses showed increased ORs for AML with several exposure metrics, although patterns were unclear; neither continuous exposure metrics nor spline analyses gave increased risks. ORs were highest in terminal workers, particularly for Tanker Drivers. No relationship was found between benzene exposure and risk of CLL, although the Australian study showed increased risks in refinery workers. Conclusion: Overall, this study does not persuasively demonstrate a risk between benzene and AML. A previously reported strong relationship between myelodysplastic syndrome (MDS) (potentially previously reported as AML) at our study's low benzene levels suggests that MDS may be the more relevant health risk for lower exposure. Higher CLL risks in refinery workers may be due to more diverse exposures than benzene alone. PMID:24357793

  14. INCIDENCE OF ACUTE MYELOID LEUKEMIA AFTER BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Caterina Giovanna Valentini

    2011-12-01

    Full Text Available Breast cancer is the most frequent cancer among women and the leading cause of death among middle-aged women. Early detection by mammography screening and improvement of therapeutic options have increased breast cancer survival rates, with the consequence that late side effects of cancer treatment become increasingly important. In particular, patients treated with adjuvant chemotherapy regimens, commonly including alkylating agents and anthracyclines, are at increased risk of developing leukemia, further enhanced by the use of radiotherapy. In the last few years also the use of growth factors seems to increase the risk of secondary leukemia. The purpose of this review is to update epidemiology of therapy-related myeloid neoplasms occurring in breast cancer patients

  15. Vav promotes differentiation of human tumoral myeloid precursors

    International Nuclear Information System (INIS)

    Bertagnolo, Valeria; Brugnoli, Federica; Mischiati, Carlo; Sereni, Alessia; Bavelloni, Alberto; Carini, Cinzia; Capitani, Silvano

    2005-01-01

    Vav is one of the genetic markers that correlate with the differentiation of hematopoietic cells. In T and B cells, it appears crucial for both development and functions, while, in non-lymphoid hematopoietic cells, Vav seems not involved in cell maturation, but rather in the response of mature cells to agonist-dependent proliferation and phagocytosis. We have previously demonstrated that the amount and the tyrosine phosphorylation of Vav are up-regulated in both whole cells and nuclei of tumoral promyelocytes induced to granulocytic maturation by ATRA and that tyrosine-phosphorylated Vav does not display any ATRA-induced GEF activity but contributes to the regulation of PI 3-K activity. In this study, we report that Vav accumulates in nuclei of ATRA-treated APL-derived cells and that the down-modulation of Vav prevents differentiation of tumoral promyelocytes, indicating that it is a key molecule in ATRA-dependent myeloid maturation. On the other hand, the overexpression of Vav induces an increased expression of surface markers of granulocytic differentiation without affecting the maturation-related changes of the nuclear morphology. Consistent with an effect of Vav on the transcriptional machinery, array profiling shows that the inhibition of the Syk-dependent tyrosine phosphorylation of Vav reduces the number of ATRA-induced genes. Our data support the unprecedented notion that Vav plays crucial functions in the maturation process of myeloid cells, and suggest that Vav can be regarded as a potential target for the therapeutic treatment of myeloproliferative disorders

  16. Children's Oncology Group's 2013 blueprint for research: acute myeloid leukemia.

    Science.gov (United States)

    Gamis, Alan S; Alonzo, Todd A; Perentesis, John P; Meshinchi, Soheil

    2013-06-01

    For the 365 children diagnosed with acute myeloid leukemia in the US annually, 5-year survival for patients on COG trials with low, intermediate, and high risk disease is 83%, 62%, and 23%, respectively. Recent advances include improved therapeutic stratification, improved survival with dose intensification, and further elucidation of the heterogeneity specific to childhood AML. These discoveries now guide current strategy incorporating targeted agents to pathways specific to childhood AML as well as evaluating methods to increase the sensitivity of the leukemic stem cell, first in Phase II feasibility trials followed by Phase III efficacy trials of the most promising agents. Acute myeloid leukemia in children, though with similar subgroups to adults, remains uniquely different based upon quite different prevalence of subtypes as well as overall response to therapy. The Children's Oncology Group's research agenda builds upon earlier efforts to better elucidate the leukemogenic steps distinct to childhood AML in order to more scientifically develop and test novel therapeutic approaches to the treatment and ultimate cure for children with this disorder. Pediatr Blood Cancer 2013; 60: 964-971. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

  17. Air traffic control activity increases attention capacity in air traffic controllers.

    Science.gov (United States)

    Ribas, Valdenilson Ribeiro; Martins, Hugo André de Lima; Amorim, Gutemberg Guerra; Ribas, Renata de Melo Guerra; de Almeida, Cláudia Ângela Vilela; Ribas, Valéria Ribeiro; de Vasconcelos, Carlos Augusto Carvalho; Lima, Murilo Duarte Costa; Sougey, Everton Botelho; de Castro, Raul Manhães

    2010-01-01

    Air traffic controllers simultaneously develop complex and multiple tasks in the course of their activities. In this context, concern is raised over the high level of attention needed by these professionals which can ultimately be affected by stress and fatigue. The objective of this study was to assess attention level in air traffic controllers (ATCo). 45 flight protection professionals were evaluated, comprising 30 ATCo, subdivided into ATCo with ten or more years in the profession (ATCo≥10, n=15) and ATCo with less than ten years in the profession (ATCo air traffic control activity after ten years may be associated with a high level of attention.

  18. Hypercaloric diets with increased meal frequency, but not meal size, increase intrahepatic triglycerides: a randomized controlled trial.

    Science.gov (United States)

    Koopman, Karin E; Caan, Matthan W A; Nederveen, Aart J; Pels, Anouk; Ackermans, Mariette T; Fliers, Eric; la Fleur, Susanne E; Serlie, Mireille J

    2014-08-01

    American children consume up to 27% of calories from high-fat and high-sugar snacks. Both sugar and fat consumption have been implicated as a cause of hepatic steatosis and obesity but the effect of meal pattern is largely understudied. We hypothesized that a high meal frequency, compared to consuming large meals, is detrimental in the accumulation of intrahepatic and abdominal fat. To test this hypothesis, we randomized 36 lean, healthy men to a 40% hypercaloric diet for 6 weeks or a eucaloric control diet and measured intrahepatic triglyceride content (IHTG) using proton magnetic resonance spectroscopy ((1) H-MRS), abdominal fat using magnetic resonance imaging (MRI), and insulin sensitivity using a hyperinsulinemic euglycemic clamp with a glucose isotope tracer before and after the diet intervention. The caloric surplus consisted of fat and sugar (high-fat-high-sugar; HFHS) or sugar only (high-sugar; HS) and was consumed together with, or between, the three main meals, thereby increasing meal size or meal frequency. All hypercaloric diets similarly increased body mass index (BMI). Increasing meal frequency significantly increased IHTG (HFHS mean relative increase of 45%; P = 0.016 and HS mean relative increase of 110%; P = 0.047), whereas increasing meal size did not (2-way analysis of variance [ANOVA] size versus frequency P = 0.03). Abdominal fat increased in the HFHS-frequency group (+63.3 ± 42.8 mL; P = 0.004) and tended to increase in the HS-frequency group (+46.5 ± 50.7 mL; P = 0.08). Hepatic insulin sensitivity tended to decrease in the HFHS-frequency group while peripheral insulin sensitivity was not affected. A hypercaloric diet with high meal frequency increased IHTG and abdominal fat independent of caloric content and body weight gain, whereas increasing meal size did not. This study suggests that snacking, a common feature in the Western diet, independently contributes to hepatic steatosis and obesity. ( www

  19. Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

    International Nuclear Information System (INIS)

    Eriksson, A; Österroos, A; Hassan, S; Gullbo, J; Rickardson, L; Jarvius, M; Nygren, P; Fryknäs, M; Höglund, M; Larsson, R

    2015-01-01

    To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC 1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug–drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis

  20. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.

    Science.gov (United States)

    Pardanani, Animesh D; Levine, Ross L; Lasho, Terra; Pikman, Yana; Mesa, Ruben A; Wadleigh, Martha; Steensma, David P; Elliott, Michelle A; Wolanskyj, Alexandra P; Hogan, William J; McClure, Rebecca F; Litzow, Mark R; Gilliland, D Gary; Tefferi, Ayalew

    2006-11-15

    Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.

  1. A typical presentation of acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Udayakumar N

    2006-01-01

    Full Text Available A young man who presented with fever, altered sensorium and sudden onset tachypnea, is described. Arterial blood gas analysis, revealed the presence of severe high anion gap metabolic acidosis, with compensatory respiratory alkalosis and normal oxygen saturation. A detailed neurological, nephrological, biochemical and hematological evaluation, revealed the presence of Acute myeloid leukemia, with lactic acidosis and hyponatremia. There are very few reports of presentation of leukemia as lactic acidosis. This case report highlights the need for emergency room physicians, to consider the possibility of lactic acidosis, as one of the causes of high anion gap acidosis and to meticulously investigate the cause of lactic acidosis. We describe a rare clinical instance of lactic acidosis as the presenting manifestation of Acute myeloid leukemia.

  2. [An immunological approach to acute myeloid leukaemia].

    Science.gov (United States)

    González, B; Bueno, D; Rubio, P M; San Román, S; Plaza, D; Sastre, A; García-Miguel, P; Fernández, L; Valentín, J; Martínez, I; Pérez-Martínez, A

    2016-04-01

    Acute myeloid leukaemia (AML) is the second haematological malignancy in the paediatric population, and one of the leading causes of childhood cancer mortality. Survival is currently around 60%, with no improvement in last decades, suggesting that new therapeutic approaches are needed. The anti-leukaemia effect mediated by the lymphocytes and natural killer (NK) cells of the immune system has been established in haematopoietic stem cell transplantation, and also as adoptive immunotherapy after consolidation chemotherapy schemes. A retrospective study was conducted on the clinical characteristics of patients diagnosed and treated for AML in our centre during 1996-2014. The mean fluorescence intensities of HLA-I, MICA/B and ULBP1-4, ligands for NK cell receptors, were also analysed in ten new diagnosed leukaemia cases, five myeloid and five lymphoid. A total of 67 patients were used in this analysis. With a median follow up of 25 months, the event-free survival was 62% (95% CI: 55-67). Secondary AML, non-M3 phenotype, and the absence of favourable cytogenetic markers had a lower survival. The probability of relapse was 38% (95% CI: 31-45). The expression of HLA-I and ULBP-4 was significantly lower in myeloid than in lymphoid blast cells. Our clinical results are similar to those described in the literature. Survival did not significantly change in recent decades, and the likelihood of relapse remains high. Myeloid blasts might be more susceptible to the cytotoxicity of NK cells through their lower expression of HLA-I. NK therapy strategies in minimal disease situation could be effective, as reported by other groups. Copyright © 2015 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  3. Splenic irradiation in chronic myeloid leukemia

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    Hukku, S.; Baboo, H.A.; Venkataratnam, S.; Vidyasagar, M.S.; Patel, N.L. (Department of Radiation Therapy, Gujarat Cancer Research Institute, Ahmedabad, India)

    1983-01-01

    Results of splenic irradiation as the initial and only method of treatment are reported in 25 patients with chronic myeloid leukemia. Peripheral remission was induced in all the patients. Induction was achieved after a short period of 11 to 30 days in the majority of the patients, the longest period being 40 days. Several patients were in remission 9 months after treatment. The results are compared with those obtained by chemotherapy. Some advantages of splenic irradiation over chemotherapy are emphasized.

  4. Effects of low dose rate irradiation on induction of myeloid leukemia in mice

    International Nuclear Information System (INIS)

    Furuse, Takeshi

    1999-01-01

    We investigated the induction of myeloid leukemia and other kinds of neoplasias in C3H male mice irradiated at several dose rate levels. We compared the incidence of neoplasias among these groups, obtained dose and dose rate effectiveness factors (DDREF) for myeloid leukemia. C3H/He male mice were exposed to whole body gamma-ray irradiation at 8 weeks of age. All mice were maintained for their entire life span and teh pathologically examined after their death. Radiation at a high dose-rate of 882 mGy/min (group H), a medium dose-rate of 95.6 mGy/min (group M), and low dose-rates of 0.298 mGy/min (group L-A), 0.067 mGy/min (group L-B) or 0.016 mGy/min (group L-C) were delivered from 137 Cs sources. The mice in group L were irradiated continuously for 22 hours daily up to total doses of 1, 2, 3, 4, 10 Gy over a period of 3 days to 200 days. As for the induction of neoplasias, myeloid leukemia developed significantly more frequently in irradiated groups than in unirradiated groups. The time distribution of mice dying from myeloid leukemia did not show a difference between groups H and L. The incidence of myeloid leukemia showed a greater increase in the high dose-rate groups than in the low and medium dose-rate groups in the dose range over 2 Gy, it also showed significant increases in the groups irradiated with 1 Gy of various dose rate, but the difference between these groups was not clear. These dose effect curves had their highest values on each curve at about 3 Gy. We obtained DDREF values of 2-3 by linear fittings for their dose response curves of dose ranges in which leukemia incidences were increasing. (author)

  5. Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.

    Science.gov (United States)

    Chiasson, Valorie L; Bounds, Kelsey R; Chatterjee, Piyali; Manandhar, Lochana; Pakanati, Abhinandan R; Hernandez, Marcos; Aziz, Bilal; Mitchell, Brett M

    2018-01-01

    The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA. © 2017 American Heart Association, Inc.

  6. [Management of the cardiovascular disease risk during nilotinib treatment in chronic myeloid leukemia: 2015 recommendations from the France Intergroupe des Leucémies Myéloïdes Chroniques].

    Science.gov (United States)

    Rea, Delphine; Ame, Shanti; Charbonnier, Aude; Coiteux, Valérie; Cony-Makhoul, Pascale; Escoffre-Barbe, Martine; Etienne, Gabriel; Gardembas, Martine; Guerci-Bresler, Agnès; Legros, Laurence; Nicolini, Franck; Tulliez, Michel; Hermet, Eric; Huguet, Françoise; Johnson-Ansah, Hyacinthe; Lapusan, Simona; Quittet, Philippe; Rousselot, Philippe; Mahon, François-Xavier; Messas, Emmanuel

    2016-02-01

    Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 2nd generation tyrosine kinase inhibitor nilotinib is licensed for the treatment of chronic myeloid leukemia with resistance or intolerance to imatinib and newly diagnosed chronic phase-chronic myeloid leukemia. Nilotinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of nilotinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in nilotinib-treated patients. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  7. A novel application of furazolidone: anti-leukemic activity in acute myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Xueqing Jiang

    Full Text Available Acute myeloid leukemia (AML is the most common malignant myeloid disorder of progenitor cells in myeloid hematopoiesis and exemplifies a genetically heterogeneous disease. The patients with AML also show a heterogeneous response to therapy. Although all-trans retinoic acid (ATRA has been successfully introduced to treat acute promyelocytic leukemia (APL, it is rather ineffective in non-APL AML. In our present study, 1200 off-patent marketed drugs and natural compounds that have been approved by the Food and Drug Administration (FDA were screened for anti-leukemia activity using the retrovirus transduction/transformation assay (RTTA. Furazolidone (FZD was shown to inhibit bone marrow transformation mediated by several leukemia fusion proteins, including AML1-ETO. Furazolidone has been used in the treatment of certain bacterial and protozoan infections in human and animals for more than sixty years. We investigated the anti-leukemic activity of FZD in a series of AML cells. FZD displayed potent antiproliferative properties at submicromolar concentrations and induced apoptosis in AML cell lines. Importantly, FZD treatment of certain AML cells induced myeloid cell differentiation by morphology and flow cytometry for CD11b expression. Furthermore, FZD treatment resulted in increased stability of tumor suppressor p53 protein in AML cells. Our in vitro results suggest furazolidone as a novel therapeutic strategy in AML patients.

  8. Sacral Myeloid Sarcoma Manifesting as Radiculopathy in a Pediatric Patient: An Unusual Form of Myeloid Leukemia Relapse

    Directory of Open Access Journals (Sweden)

    Joana Ruivo Rodrigues

    2018-01-01

    Full Text Available Myeloid sarcoma (MS, granulocytic sarcoma or chloroma, is defined as a localized extramedullary mass of blasts of granulocytic lineage with or without maturation, occurring outside the bone marrow. MS can be diagnosed concurrently with acute myeloid leukemia (AML or myelodysplastic syndrome (MDS. The authors report a case of sacral MS occurring as a relapse of myeloid leukemia in a 5-year-old girl who was taken to the emergency department with radiculopathy symptoms.

  9. The Danish National Chronic Myeloid Neoplasia Registry

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    Bak M

    2016-10-01

    Full Text Available Marie Bak,1 Else Helene Ibfelt,2 Thomas Stauffer Larsen,3 Dorthe Rønnov-Jessen,4 Niels Pallisgaard,5 Ann Madelung,6 Lene Udby,1 Hans Carl Hasselbalch,1 Ole Weis Bjerrum,7 Christen Lykkegaard Andersen1,7 1Department of Hematology, Zealand University Hospital, University of Copenhagen, Roskilde, 2Research Centre for Prevention and Health, Rigshospitalet Glostrup, University of Copenhagen, Glostrup, 3Department of Hematology, Odense University Hospital, Odense, 4Department of Hematology, Vejle Hospital, Vejle, 5Department of Surgical Pathology, Zealand University Hospital, University of Copenhagen, Roskilde, 6Department of Surgical Pathology, Zealand University Hospital, University of Copenhagen, Næstved, 7Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Aim: The Danish National Chronic Myeloid Neoplasia Registry (DCMR is a population-based clinical quality database, introduced to evaluate diagnosis and treatment of patients with chronic myeloid malignancies. The aim is to monitor the clinical quality at the national, regional, and hospital departmental levels and serve as a platform for research. Study population: The DCMR has nationwide coverage and contains information on patients diagnosed at hematology departments from January 2010 onward, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, unclassifiable myeloproliferative neoplasms, chronic myelomonocytic leukemia, and chronic myeloid leukemia. Main variables: Data are collected using standardized registration forms (so far up to four forms per patient, which are consecutively filled out online at time of diagnosis, after 2-year and 5-year follow-ups, and at end of follow-up. The forms include variables that describe clinical/paraclinical assessments, treatment, disease progression, and survival – disease-specific variables – as well as variables that are identical for all chronic myeloid malignancies. Descriptive

  10. Striving for Group Agency: Threat to Personal Control Increases the Attractiveness of Agentic Groups

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    Janine eStollberg

    2015-05-01

    Full Text Available When their sense of personal control is threatened people try to restore perceived control through the social self. We propose that it is the perceived agency of ingroups that provides the self with a sense of control. In three experiments, we for the first time tested the hypothesis that threat to personal control increases the attractiveness of being part or joining those groups that are perceived as coherent entities engaging in coordinated group goal pursuit (agentic groups but not of those groups whose agency is perceived to be low. Consistent with this hypothesis we found in Study 1 (N = 93 that threat to personal control increased ingroup identification only with task groups, but not with less agentic types of ingroups that were made salient simultaneously. Furthermore, personal control threat increased a sense of collective control and support within the task group, mediated through task-group identification (indirect effects. Turning to groups people are not (yet part of, Study 2 (N = 47 showed that personal control threat increased relative attractiveness ratings of small groups as possible future ingroups only when the relative agency of small groups was perceived to be high. Perceived group homogeneity or social power did not moderate the effect. Study 3 (N = 78 replicated the moderating role of perceived group agency for attractiveness ratings of entitative groups, whereas perceived group status did not moderate the effect. These findings extend previous research on group-based control, showing that perceived agency accounts for group-based responses to threatened control.

  11. Wireless sensing and vibration control with increased redundancy and robustness design.

    Science.gov (United States)

    Li, Peng; Li, Luyu; Song, Gangbing; Yu, Yan

    2014-11-01

    Control systems with long distance sensor and actuator wiring have the problem of high system cost and increased sensor noise. Wireless sensor network (WSN)-based control systems are an alternative solution involving lower setup and maintenance costs and reduced sensor noise. However, WSN-based control systems also encounter problems such as possible data loss, irregular sampling periods (due to the uncertainty of the wireless channel), and the possibility of sensor breakdown (due to the increased complexity of the overall control system). In this paper, a wireless microcontroller-based control system is designed and implemented to wirelessly perform vibration control. The wireless microcontroller-based system is quite different from regular control systems due to its limited speed and computational power. Hardware, software, and control algorithm design are described in detail to demonstrate this prototype. Model and system state compensation is used in the wireless control system to solve the problems of data loss and sensor breakdown. A positive position feedback controller is used as the control law for the task of active vibration suppression. Both wired and wireless controllers are implemented. The results show that the WSN-based control system can be successfully used to suppress the vibration and produces resilient results in the presence of sensor failure.

  12. Enhanced attention to context: An intervention that increases perceived control in mild depression.

    Science.gov (United States)

    Msetfi, R M; Brosnan, L; Cavus, H A

    2016-01-01

    People perceive that they have control over events to the extent that the same events do not occur outside of their control, randomly, in the environment or context. Therefore, perceived control should be enhanced if there is a large contrast between one's own control and the control that the context itself seems to exert over events. Given that depression is associated with low perceived control, we tested the hypothesis that enhanced attentional focus to context will increase perceived control in people with and without depression. A total of 106 non-depressed and mildly depressed participants completed a no control zero-contingency task with low and high outcome probability conditions. In the experimental context-focus group, participants were instructed to attend to the context, whereas in the control group, participants were instructed to attend to their thoughts. Irrespective of attentional focus, non-depressed participants displayed illusory control. However, people with mild depression responded strongly to the attention focus manipulation. In the control group, they evidenced low perceived control with classic depressive realism effects. In the experimental group, when asked to focus on the context in which events took place, participants with mild depression displayed enhanced perceived control or illusory control, similar to non-depressed participants. Findings are discussed in relation to whether depression effects on perceived control represent tendencies towards realism or attentional aspects of depressive thoughts.

  13. Automatic control of load increases power and efficiency in a microbial fuel cell

    Energy Technology Data Exchange (ETDEWEB)

    Premier, Giuliano C.; Kim, Jung Rae; Michie, Iain [Sustainable Environment Research Centre (SERC), Faculty of Advanced Technology, University of Glamorgan, Pontypridd, Mid-Glamorgan CF37 1DL (United Kingdom); Dinsdale, Richard M.; Guwy, Alan J. [Sustainable Environment Research Centre (SERC), Faculty of Health, Sport and Science, University of Glamorgan, Pontypridd, Mid-Glamorgan CF37 1DL (United Kingdom)

    2011-02-15

    Increasing power production and coulombic efficiency (CE) of microbial fuel cells (MFCs) is a common research ambition as the viability of the technology depends to some extent on these measures of performance. As MFCs are typically time varying systems, comparative studies of controlled and un-controlled external load impedance are needed to show if control affects the biocatalyst development and hence MFC performance. The application of logic based control of external load resistance is shown to increase the power generated by the MFC, when compared to an equivalent system which has a static resistive load. The controlled MFC generated 1600 {+-} 400 C, compared to 300 {+-} 10 C with an otherwise replicate fixed load MFC system. The use of a parsimonious gradient based control was able to increase the CE to within the range of 15.1-22.7%, while the CE for a 200 {omega} statically loaded MFC lay in the range 3.3-3.7%. The controlled MFC improves the electrogenic anodic biofilm selection for power production, indicating that greater power and substrate conversion can be achieved by controlling load impedance. Load control ensured sustainable current demand, applied microbial selection pressures and provided near-optimal impedance for power transference, compared to the un-controlled system. (author)

  14. Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization

    Science.gov (United States)

    Stafford, Jason H.; Hirai, Takahisa; Deng, Lei; Chernikova, Sophia B.; Urata, Kimiko; West, Brian L.; Brown, J. Martin

    2016-01-01

    Background Glioblastoma (GBM) may initially respond to treatment with ionizing radiation (IR), but the prognosis remains extremely poor because the tumors invariably recur. Using animal models, we previously showed that inhibiting stromal cell–derived factor 1 signaling can prevent or delay GBM recurrence by blocking IR-induced recruitment of myeloid cells, specifically monocytes that give rise to tumor-associated macrophages. The present study was aimed at determining if inhibiting colony stimulating factor 1 (CSF-1) signaling could be used as an alternative strategy to target pro-tumorigenic myeloid cells recruited to irradiated GBM. Methods To inhibit CSF-1 signaling in myeloid cells, we used PLX3397, a small molecule that potently inhibits the tyrosine kinase activity of the CSF-1 receptor (CSF-1R). Combined IR and PLX3397 therapy was compared with IR alone using 2 different human GBM intracranial xenograft models. Results GBM xenografts treated with IR upregulated CSF-1R ligand expression and increased the number of CD11b+ myeloid-derived cells in the tumors. Treatment with PLX3397 both depleted CD11b+ cells and potentiated the response of the intracranial tumors to IR. Median survival was significantly longer for mice receiving combined therapy versus IR alone. Analysis of myeloid cell differentiation markers indicated that CSF-1R inhibition prevented IR-recruited monocyte cells from differentiating into immunosuppressive, pro-angiogenic tumor-associated macrophages. Conclusion CSF-1R inhibition may be a promising strategy to improve GBM response to radiotherapy. PMID:26538619

  15. UV light B-mediated inhibition of skin catalase activity promotes Gr-1+ CD11b+ myeloid cell expansion.

    Science.gov (United States)

    Sullivan, Nicholas J; Tober, Kathleen L; Burns, Erin M; Schick, Jonathan S; Riggenbach, Judith A; Mace, Thomas A; Bill, Matthew A; Young, Gregory S; Oberyszyn, Tatiana M; Lesinski, Gregory B

    2012-03-01

    Skin cancer incidence and mortality are higher in men compared with women, but the causes of this sex discrepancy remain largely unknown. UV light exposure induces cutaneous inflammation and neutralizes cutaneous antioxidants. Gr-1(+)CD11b(+) myeloid cells are heterogeneous bone marrow-derived cells that promote inflammation-associated carcinogenesis. Reduced activity of catalase, an antioxidant present in the skin, has been associated with skin carcinogenesis. We used the outbred, immune-competent Skh-1 hairless mouse model of UVB-induced inflammation and non-melanoma skin cancer to further define sex discrepancies in UVB-induced inflammation. Our results demonstrated that male skin had relatively lower baseline catalase activity, which was inhibited following acute UVB exposure in both sexes. Further analysis revealed that skin catalase activity inversely correlated with splenic Gr-1(+)CD11b(+) myeloid cell percentage. Acute UVB exposure induced Gr-1(+)CD11b(+) myeloid cell skin infiltration, which was inhibited to a greater extent in male mice by topical catalase treatment. In chronic UVB studies, we demonstrated that the percentage of splenic Gr-1(+)CD11b(+) myeloid cells was 55% higher in male tumor-bearing mice compared with their female counterparts. Together, our findings indicate that lower skin catalase activity in male mice may at least in part contribute to increased UVB-induced generation of Gr-1(+)CD11b(+) myeloid cells and subsequent skin carcinogenesis.

  16. CONTROLLING AS A MECHANISM TO INCREASE THE EFFICIENCY OF MANAGEMENT ENTERPRISES OF FUEL-ENERGY COMPLEX

    Directory of Open Access Journals (Sweden)

    M. A. Ostashkin

    2013-01-01

    Full Text Available This article discusses the possibility of application of controlling as mechanism of increasing the efficiency of management of enterprises of fuel- energy complex. The research was conducted on the materials of the JSC «Gazprom».

  17. The method to increase an adequacy and exactitude of the tracking of controlled airplane flight

    Directory of Open Access Journals (Sweden)

    В. М. Васильєв

    2003-03-01

    Full Text Available The method to increase the adequacy and exactitude of trajectory estimates for tracking of controlled flight is proposed. The method of a solution of a non-linearity problem is also offered when imitate in trajectory estimation algorithm a control signal which includes nonlinear functions of restriction. The results of computer simulation are demonstrated

  18. The rate of spontaneous mutations in human myeloid cells

    International Nuclear Information System (INIS)

    Araten, David J.; Krejci, Ondrej; DiTata, Kimberly; Wunderlich, Mark; Sanders, Katie J.; Zamechek, Leah; Mulloy, James C.

    2013-01-01

    Highlights: • We provide the first measurement of the mutation rate (μ) in human myeloid cells. • μ is measured to be 3.6–23 × 10 −7 per cell division. • The AML-ETO and MLL-AF9 fusions do not seem to increase μ. • Cooperating mutations in NRAS, FLT3 and p53 not seem to increase μ. • Hypermutability may be required to explain leukemogenesis. - Abstract: The mutation rate (μ) is likely to be a key parameter in leukemogenesis, but historically, it has been difficult to measure in humans. The PIG-A gene has some advantages for the detection of spontaneous mutations because it is X-linked, and therefore only one mutation is required to disrupt its function. Furthermore, the PIG-A-null phenotype is readily detected by flow cytometry. Using PIG-A, we have now provided the first in vitro measurement of μ in myeloid cells, using cultures of CD34+ cells that are transduced with either the AML-ETO or the MLL-AF9 fusion genes and expanded with cytokines. For the AML-ETO cultures, the median μ value was ∼9.4 × 10 −7 (range ∼3.6–23 × 10 −7 ) per cell division. In contrast, few spontaneous mutations were observed in the MLL-AF9 cultures. Knockdown of p53 or introduction of mutant NRAS or FLT3 alleles did not have much of an effect on μ. Based on these data, we provide a model to predict whether hypermutability must occur in the process of leukemogenesis

  19. Mesenchymal Stem Cells (MSC Regulate Activation of Granulocyte-Like Myeloid Derived Suppressor Cells (G-MDSC in Chronic Myeloid Leukemia Patients.

    Directory of Open Access Journals (Sweden)

    Cesarina Giallongo

    Full Text Available It is well known that mesenchymal stem cells (MSC have a role in promotion of tumor growth, survival and drug-resistance in chronic myeloid leukemia (CML. Recent reports indicated that a subpopulation of myeloid cells, defined as granulocyte-like myeloid-derived suppressor cells (G-MDSC is increased in these patients. So far, the role of MSC in MDSC expansion and activation into the BM microenvironment remains unexplored. To address this question, here we use a specific experimental model in vitro, co-culturing MSC with peripheral blood mononucleated cells (PBMC from normal individuals, in order to generate MSC-educated G-MDSC. Although MSC of healthy donors (HD and CML patients were able to generate the same amount of MDSC, only CML-MSC-educated G-MDSC exhibited suppressive ability on autologous T lymphocytes. In addition, compared with HD-MSC, CML-MSC over-expressed some immunomodulatory factors including TGFβ, IL6 and IL10, that could be involved in MDSC activation. CML-MSC-educated G-MDSC expressed higher levels of ARG1, TNFα, IL1β, COX2 and IL6 than G-MDSC isolated from co-culture with HD-MSC. Our data provide evidence that CML-MSC may play a critical role in tumor microenvironment by orchestrating G-MDSC activation and regulating T lymphocytes-mediated leukemia surveillance, thus contributing to CML immune escape.

  20. Mesenchymal Stem Cells (MSC) Regulate Activation of Granulocyte-Like Myeloid Derived Suppressor Cells (G-MDSC) in Chronic Myeloid Leukemia Patients.

    Science.gov (United States)

    Giallongo, Cesarina; Romano, Alessandra; Parrinello, Nunziatina Laura; La Cava, Piera; Brundo, Maria Violetta; Bramanti, Vincenzo; Stagno, Fabio; Vigneri, Paolo; Chiarenza, Annalisa; Palumbo, Giuseppe Alberto; Tibullo, Daniele; Di Raimondo, Francesco

    2016-01-01

    It is well known that mesenchymal stem cells (MSC) have a role in promotion of tumor growth, survival and drug-resistance in chronic myeloid leukemia (CML). Recent reports indicated that a subpopulation of myeloid cells, defined as granulocyte-like myeloid-derived suppressor cells (G-MDSC) is increased in these patients. So far, the role of MSC in MDSC expansion and activation into the BM microenvironment remains unexplored. To address this question, here we use a specific experimental model in vitro, co-culturing MSC with peripheral blood mononucleated cells (PBMC) from normal individuals, in order to generate MSC-educated G-MDSC. Although MSC of healthy donors (HD) and CML patients were able to generate the same amount of MDSC, only CML-MSC-educated G-MDSC exhibited suppressive ability on autologous T lymphocytes. In addition, compared with HD-MSC, CML-MSC over-expressed some immunomodulatory factors including TGFβ, IL6 and IL10, that could be involved in MDSC activation. CML-MSC-educated G-MDSC expressed higher levels of ARG1, TNFα, IL1β, COX2 and IL6 than G-MDSC isolated from co-culture with HD-MSC. Our data provide evidence that CML-MSC may play a critical role in tumor microenvironment by orchestrating G-MDSC activation and regulating T lymphocytes-mediated leukemia surveillance, thus contributing to CML immune escape.

  1. Prognostic value of regulatory T cells in newly diagnosed chronic myeloid leukemia patients.

    Science.gov (United States)

    Zahran, Asmaa M; Badrawy, Hosny; Ibrahim, Abeer

    2014-08-01

    Chronic myeloid leukemia (CML) is a clonal disease, characterized by a reciprocal t(9, 22) that results in a chimeric BCR/ABL fusion gene. Regulatory T cells (Tregs) constitute the main cell population that enables cancer cells to evade immune surveillance. The purpose of our study was to investigate the level of Tregs in newly diagnosed CML patients and to correlate it with the patients' clinical, laboratory and molecular data. We also aimed to assess the effect of treatment using tyrosine kinase inhibitor (TKI) on Treg levels. Tregs were characterized and quantified by flow cytometry in 63 newly diagnosed CML patients and 40 healthy controls. TKI was used in 45 patients with chronic phase CML, and the response to therapy was correlated with baseline Treg levels. The percentages of Tregs were significantly increased in CML patients compared to the controls. Treg numbers were significantly lower in patients with chronic phase CML versus the accelerated and blast phases, and were significantly lower in patients with complete molecular remission (CMR) compared to those patients without CMR. Tregs may play a role in the maintenance of CML. Moreover, the decrease of their levels in patients with CMR suggests that Tregs might have a clinical value in evaluating the effects of therapy.

  2. Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version

    Science.gov (United States)

    Acute myeloid leukemia (AML), juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) account for about 20% of childhood myeloid leukemias. Other myeloid malignancies include transient abnormal myelopoiesis and myelodysplastic syndrome. Get detailed information about the classification, clinical presentation, diagnostic and molecular evaluation, prognosis, and treatment of newly diagnosed and recurrent disease in this summary for clinicians.

  3. Visual working memory capacity increases between ages 3 and 8 years, controlling for gains in attention, perception, and executive control.

    Science.gov (United States)

    Pailian, Hrag; Libertus, Melissa E; Feigenson, Lisa; Halberda, Justin

    2016-08-01

    Research in adults has aimed to characterize constraints on the capacity of Visual Working Memory (VWM), in part because of the system's broader impacts throughout cognition. However, less is known about how VWM develops in childhood. Existing work has reached conflicting conclusions as to whether VWM storage capacity increases after infancy, and if so, when and by how much. One challenge is that previous studies did not control for developmental changes in attention and executive processing, which also may undergo improvement. We investigated the development of VWM storage capacity in children from 3 to 8 years of age, and in adults, while controlling for developmental change in exogenous and endogenous attention and executive control. Our results reveal that, when controlling for improvements in these abilities, VWM storage capacity increases across development and approaches adult-like levels between ages 6 and 8 years. More generally, this work highlights the value of estimating working memory, attention, perception, and decision-making components together.

  4. Active Choice and Financial Incentives to Increase Rates of Screening Colonoscopy-A Randomized Controlled Trial.

    Science.gov (United States)

    Mehta, Shivan J; Feingold, Jordyn; Vandertuyn, Matthew; Niewood, Tess; Cox, Catherine; Doubeni, Chyke A; Volpp, Kevin G; Asch, David A

    2017-11-01

    Behavioral economic approaches could increase uptake for colorectal cancer screening. We performed a randomized controlled trial of 2245 employees to determine whether an email containing a phone number for scheduling (control), an email with the active choice to opt in or opt out (active choice), or the active choice email plus a $100 incentive (financial incentive) increased colonoscopy completion within 3 months. Higher proportions of participants in the financial incentive group underwent screening (3.7%) than in the control (1.6%) or active choice groups (1.5%) (P = .01 and P < .01). We found no difference in uptake of screening between the active choice and control groups (P = .88). The $100 conditional incentive modestly but significantly increased colonoscopy use. ClinicalTrials.gov no: NCT02660671. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  5. Assessing the miRNA sponge potential of RUNX1T1 in t(8;21) acute myeloid leukemia

    DEFF Research Database (Denmark)

    Junge, Alexander; Zandi, Roza; Havgaard, Jakob Hull

    2017-01-01

    t(8;21) acute myeloid leukemia (AML) is characterized by a translocation between chromosomes 8 and 21 and formation of a distinctive RUNX1-RUNX1T1 fusion transcript. This translocation places RUNX1T1 under control of the RUNX1 promoter leading to a pronounced upregulation of RUNX1T1 transcripts...

  6. Impaired B cell immunity in acute myeloid leukemia patients after chemotherapy.

    Science.gov (United States)

    Goswami, Meghali; Prince, Gabrielle; Biancotto, Angelique; Moir, Susan; Kardava, Lela; Santich, Brian H; Cheung, Foo; Kotliarov, Yuri; Chen, Jinguo; Shi, Rongye; Zhou, Huizhi; Golding, Hana; Manischewitz, Jody; King, Lisa; Kunz, Lauren M; Noonan, Kimberly; Borrello, Ivan M; Smith, B Douglas; Hourigan, Christopher S

    2017-07-10

    Changes in adaptive immune cells after chemotherapy in adult acute myeloid leukemia (AML) may have implications for the success of immunotherapy. This study was designed to determine the functional capacity of the immune system in adult patients with AML who have completed chemotherapy and are potential candidates for immunotherapy. We used the response to seasonal influenza vaccination as a surrogate for the robustness of the immune system in 10 AML patients in a complete remission post-chemotherapy and performed genetic, phenotypic, and functional characterization of adaptive immune cell subsets. Only 2 patients generated protective titers in response to vaccination, and a majority of patients had abnormal frequencies of transitional and memory B-cells. B-cell receptor sequencing showed a B-cell repertoire with little evidence of somatic hypermutation in most patients. Conversely, frequencies of T-cell populations were similar to those seen in healthy controls, and cytotoxic T-cells demonstrated antigen-specific activity after vaccination. Effector T-cells had increased PD-1 expression in AML patients least removed from chemotherapy. Our results suggest that while some aspects of cellular immunity recover quickly, humoral immunity is incompletely reconstituted in the year following intensive cytotoxic chemotherapy for AML. The observed B-cell abnormalities may explain the poor response to vaccination often seen in AML patients after chemotherapy. Furthermore, the uncoupled recovery of B-cell and T-cell immunity and increased PD-1 expression shortly after chemotherapy might have implications for the success of several modalities of immunotherapy.

  7. BAG1: the guardian of anti-apoptotic proteins in acute myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Sanja Aveic

    Full Text Available BCL2 associated Athano-Gene 1 (BAG1 is a multifunctional protein that has been described to be involved in different cell processes linked to cell survival. It has been reported as deregulated in diverse cancer types. Here, BAG1 protein was found highly expressed in children with acute myeloid leukemia at diagnosis, and in a cohort of leukemic cell lines. A silencing approach was used for determining BAG1's role in AML, finding that its down-regulation decreased expression of BCL2, BCL-XL, MCL1, and phospho-ERK1/2, all proteins able to sustain leukemia, without affecting the pro-apoptotic protein BAX. BAG1 down-regulation was also found to increase expression of BAG3, whose similar activity was able to compensate the loss of function of BAG1. BAG1/BAG3 co-silencing caused an enhanced cell predisposition to death in cell lines and also in primary AML cultures, affecting the same proteins. Cell death was CASPASE-3 dependent, was accompanied by PARP cleavage and documented by an increased release of pro-apoptotic molecules Smac/DIABLO and Cytochrome c. BAG1 was found to directly maintain BCL2 and to protect MCL1 from proteasomal degradation by controlling USP9X expression, which appeared to be its novel target. Finally, BAG1 was found able to affect leukemia cell fate by influencing the expression of anti-apoptotic proteins crucial for AML maintenance.

  8. Molecular alterations in acute myeloid leukemia and their clinical and therapeutical implications.

    Science.gov (United States)

    Infante, María Stefania; Piris, Miguel Ángel; Hernández-Rivas, José Ángel

    2018-06-09

    Acute myeloid leukaemia is the most common form of acute leukaemia, and its incidence increases with age. The disease derives from a transformed multipotent malignant haematopoietic stem cell that acquires consequent genomic alterations. The identification of recurrent cytogenetic anomalies associated with different patterns of acute myeloid leukaemia clinical presentation has led to the incorporation of genetic markers in clinical decision-making. In addition, the observation that these anomalies may mark therapeutic responses and relapse and survival rates have been incorporated into the World Health Organisation's recent molecular classification and stratification and the European Leukaemia Net, with the aim of creating prognostic categories that help rationalise better diagnosis, prognosis, re-evaluation of the disease and the combination of therapeutic protocols in order to increase the survival rate of these patients. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

  9. Lentinan: hematopoietic, immunological, and efficacy studies in a syngeneic model of acute myeloid leukemia.

    Science.gov (United States)

    McCormack, Emmet; Skavland, Jørn; Mujic, Maja; Bruserud, Øystein; Gjertsen, Bjørn Tore

    2010-01-01

    Lentinan, a beta-glucan nutritional supplement isolated from the shitake mushroom (Lentula edodes), is a biological response modifier with immunostimulatory properties. Concomitantly, the role of beta-glucans as chemoimmunotherapeutic in a number of solid cancers has been widely documented. We investigated the effects of nutritional grade lentinan upon BN rats and in a preclinical syngeneic model of acute myeloid leukemia. BN rats supplemented daily with lentinan exhibited weight gains, increased white blood cells, monocytes, and circulating cytotoxic T-cells; and had a reduction in anti-inflammatory cytokines IL-4, IL-10, and additionally IL-6. Lentinan treatment of BN rats with BNML leukemia resulted in improved cage-side health and reduced cachexia in the terminal stage of this aggressive disease. Combination of lentinan with standards of care in acute myeloid leukemia, idarubicin, and cytarabine increased average survival compared with monotherapy and reduced cachexia. These results indicate that nutritional supplementation of cancer patients with lentinan should be further investigated.

  10. Myeloid-specific deletion of NOX2 prevents the metabolic and neurologic consequences of high fat diet.

    Directory of Open Access Journals (Sweden)

    Jennifer K Pepping

    Full Text Available High fat diet-induced obesity is associated with inflammatory and oxidative signaling in macrophages that likely participates in metabolic and physiologic impairment. One key factor that could drive pathologic changes in macrophages is the pro-inflammatory, pro-oxidant enzyme NADPH oxidase. However, NADPH oxidase is a pleiotropic enzyme with both pathologic and physiologic functions, ruling out indiscriminant NADPH oxidase inhibition as a viable therapy. To determine if targeted inhibition of monocyte/macrophage NADPH oxidase could mitigate obesity pathology, we generated mice that lack the NADPH oxidase catalytic subunit NOX2 in myeloid lineage cells. C57Bl/6 control (NOX2-FL and myeloid-deficient NOX2 (mNOX2-KO mice were given high fat diet for 16 weeks, and subject to comprehensive metabolic, behavioral, and biochemical analyses. Data show that mNOX2-KO mice had lower body weight, delayed adiposity, attenuated visceral inflammation, and decreased macrophage infiltration and cell injury in visceral adipose relative to control NOX2-FL mice. Moreover, the effects of high fat diet on glucose regulation and circulating lipids were attenuated in mNOX2-KO mice. Finally, memory was impaired and markers of brain injury increased in NOX2-FL, but not mNOX2-KO mice. Collectively, these data indicate that NOX2 signaling in macrophages participates in the pathogenesis of obesity, and reinforce a key role for macrophage inflammation in diet-induced metabolic and neurologic decline. Development of macrophage/immune-specific NOX-based therapies could thus potentially be used to preserve metabolic and neurologic function in the context of obesity.

  11. Motivational incentives lead to a strong increase in lateral prefrontal activity after self-control exertion.

    Science.gov (United States)

    Luethi, Matthias S; Friese, Malte; Binder, Julia; Boesiger, Peter; Luechinger, Roger; Rasch, Björn

    2016-10-01

    Self-control is key to success in life. Initial acts of self-control temporarily impair subsequent self-control performance. Why such self-control failures occur is unclear, with prominent models postulating a loss of a limited resource vs a loss of motivation, respectively. Here, we used functional magnetic resonance imaging to identify the neural correlates of motivation-induced benefits on self-control. Participants initially exerted or did not exert self-control. In a subsequent Stroop task, participants performed worse after exerting self-control, but not if they were motivated to perform well by monetary incentives. On the neural level, having exerted self-control resulted in decreased activation in the left inferior frontal gyrus. Increasing motivation resulted in a particularly strong activation of this area specifically after exerting self-control. Thus, after self-control exertion participants showed more prefrontal neural activity without improving performance beyond baseline level. These findings suggest that impaired performance after self-control exertion may not exclusively be due to a loss of motivation. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  12. Increased alcohol use after Hurricane Ike: The roles of perceived social cohesion and social control.

    Science.gov (United States)

    Ma, Chenyi; Smith, Tony E

    2017-10-01

    Hurricane Ike, the third costliest hurricane in US history, made landfall in the Galveston Bay Area in September, 2008. Existing literature postulates that maladaptive behavior such as increased alcohol use is often exhibited by disaster survivors in coping with both disaster-related traumatic events and post-disaster stressful events. In addition, it has also been postulated that survivors' perceptions of social cohesion and social control can potentially serve to moderate such behavior. The purpose of this paper is to study such hypotheses for Hurricane Ike. In particular, we investigate the following four hypotheses: (H1) There is an increase of alcohol use by survivors of Hurricane Ike in the Galveston Bay Area; (H2) There are positive associations between both Ike-related trauma and post-Ike stress events and the increase in alcohol use; (H3) There are negative associations between both perceived social cohesion and social control and the increase in alcohol use following Ike; and finally that (H4) perceived social cohesion and social control serve to moderate the associations between both Ike-related trauma and post-Ike stress events and increased alcohol use after Ike. Using public use survey-weighted data from the Galveston Bay Recovery Study (GBRS) of Ike survivors (N = 658), we tested these hypotheses using logistic regressions controlling for other key socioeconomic variables. Our results confirm H1 and H2. Hypotheses H3 and H4 are partially confirmed with respect to social control, but show that (i) there is a positive association between perceived social cohesion and the increase in alcohol use following Ike, and that (ii) while perceived social cohesion and social control do moderate the association between post-Ike stress events and increased alcohol use, they have no effect on the association between Ike-related trauma and increased alcohol use. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Dasatinib in the treatment of imatinib refractory chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Ramchandren

    2009-05-01

    Full Text Available Radhakrishnan Ramchandren, Charles A SchifferDivision of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USAAbstract: The development of imatinib for the treatment of chronic myeloid leukemia (CML has proven to be an example of medical success in the era of targeted therapy. However, imatinib resistance or intolerance occurs in a substantial number of patients. Additionally, patients who have progressed beyond the chronic phase of CML do relatively poorly with imatinib therapy. Mechanisms of imatinib resistance include BCR-ABL point mutations resulting in decreased imatinib binding, as well as mutation-independent causes of resistance such as SRC family kinase dysregulation, BCR-ABL gene amplification, drug influx/efflux mechanisms and other poorly understood processes. The options for therapy in these patients include stem cell transplantation, imatinib dose escalation as well as the use of second-generation tyrosine kinase inhibitors. Dasatinib is a second-generation multi-kinase inhibitor with several theoretical and mechanistic advantages over imatinib. Moreover, several studies have evaluated dasatinib in patients who have progressed on imatinib therapy with encouraging results. Other novel agents such as mTOR inhibitors, bosutinib and INNO 406 have also shown promise in this setting. Although treatment options have increased, the choice of second-line therapy in patients with CML is influenced by concerns surrounding the duration of response as well as toxicity. Consequently, there is no agreed upon optimal second-line agent. This paper reviews the current data and attempts to address these issues. Keywords: chronic myeloid leukemia (CML, dasatinib, imatinib, resistance (imatinib resistance, nilotinib, tyrosine kinase inhibitor

  14. Drug Repurposing for the Treatment of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Vibeke Andresen

    2017-11-01

    Full Text Available Acute myeloid leukemia (AML is a heterogeneous disease characterized by the accumulation of immature myeloid progenitor cells in the bone marrow, compromising of normal blood cell production and ultimately resulting in bone marrow failure. With a 20% overall survival rate at 5 years and 50% in the 18- to 65-year-old age group, new medicines are needed. It is proposed that development of repurposed drugs may be a part of the new therapy needed. AML is subdivided into recurrent molecular entities based on molecular genetics increasingly accessible for precision medicine. Novel therapy developments form a basis for novel multimodality therapy and include liposomal daunorubicin/cytarabine, broad or FLT3-specific tyrosine kinase inhibitors, Bcl-2 family inhibitors, selective inhibitors of nuclear export, metabolic inhibitors, and demethylating agents. The use of non-transplant immunotherapy is in early development in AML with the exceptional re-approval of a toxin-conjugated anti-CD33. However, the full potential of small molecule inhibitors and modalities like immunological checkpoint inhibitors, immunostimulatory small molecules, and CAR-T cell therapy is unknown. Some novel therapeutics will certainly benefit AML patient subgroups; however, due to high cost, more affordable alternatives are needed globally. Also the heterogeneity of AML will likely demand a broader repertoire of therapeutic molecules. Drug repurposing or repositioning represent a source for potential therapeutics with well-known toxicity profiles and reasonable prices. This implies that biomarkers of response need to accompany the development of antileukemic therapies for sharply defined patient subgroups. We will illustrate repurposing in AML with selected examples and discuss some experimental and regulatory limitations that may obstruct this development.

  15. Tunneling Nanotubes: Intimate Communication between Myeloid Cells.

    Science.gov (United States)

    Dupont, Maeva; Souriant, Shanti; Lugo-Villarino, Geanncarlo; Maridonneau-Parini, Isabelle; Vérollet, Christel

    2018-01-01

    Tunneling nanotubes (TNT) are dynamic connections between cells, which represent a novel route for cell-to-cell communication. A growing body of evidence points TNT towards a role for intercellular exchanges of signals, molecules, organelles, and pathogens, involving them in a diverse array of functions. TNT form among several cell types, including neuronal cells, epithelial cells, and almost all immune cells. In myeloid cells (e.g., macrophages, dendritic cells, and osteoclasts), intercellular communication via TNT contributes to their differentiation and immune functions. Importantly, TNT enable myeloid cells to communicate with a targeted neighboring or distant cell, as well as with other cell types, therefore creating a complex variety of cellular exchanges. TNT also contribute to pathogen spread as they serve as "corridors" from a cell to another. Herein, we addressed the complexity of the definition and in vitro characterization of TNT in innate immune cells, the different processes involved in their formation, and their relevance in vivo . We also assess our current understanding of how TNT participate in immune surveillance and the spread of pathogens, with a particular interest for HIV-1. Overall, despite recent progress in this growing research field, we highlight that further investigation is needed to better unveil the role of TNT in both physiological and pathological conditions.

  16. Tunneling Nanotubes: Intimate Communication between Myeloid Cells

    Directory of Open Access Journals (Sweden)

    Maeva Dupont

    2018-01-01

    Full Text Available Tunneling nanotubes (TNT are dynamic connections between cells, which represent a novel route for cell-to-cell communication. A growing body of evidence points TNT towards a role for intercellular exchanges of signals, molecules, organelles, and pathogens, involving them in a diverse array of functions. TNT form among several cell types, including neuronal cells, epithelial cells, and almost all immune cells. In myeloid cells (e.g., macrophages, dendritic cells, and osteoclasts, intercellular communication via TNT contributes to their differentiation and immune functions. Importantly, TNT enable myeloid cells to communicate with a targeted neighboring or distant cell, as well as with other cell types, therefore creating a complex variety of cellular exchanges. TNT also contribute to pathogen spread as they serve as “corridors” from a cell to another. Herein, we addressed the complexity of the definition and in vitro characterization of TNT in innate immune cells, the different processes involved in their formation, and their relevance in vivo. We also assess our current understanding of how TNT participate in immune surveillance and the spread of pathogens, with a particular interest for HIV-1. Overall, despite recent progress in this growing research field, we highlight that further investigation is needed to better unveil the role of TNT in both physiological and pathological conditions.

  17. Stormwater Volume Control to Prevent Increases in Lake Flooding and Dam Failure Risk

    Science.gov (United States)

    Potter, K. W.

    2017-12-01

    Urban expansion is not often considered a major factor contributing to dam failure. But if urbanization occurs without mitigation of the hydrologic impacts, the risk of dam failure will increase. Of particular concern are increases in the volume of storm runoff resulting from increases in the extent of impervious surfaces. Storm runoff volumes are not regulated for much the U.S, and where they are, the required control is commonly less than 100%. Unmitigated increases in runoff volume due to urbanization can pose a risk to dams. A recent technical advisory committee of Dane County has recommended that the county require 100% control of stormwater volumes for new developments. The primary motivation was to prevent increases in the water levels in the Yahara Lakes, slowly draining lakes that are highly sensitive to runoff volume. The recommendations included the use of "volume trading" to achieve efficient compliance. Such recommendations should be considered for other slowly draining lakes, including those created by artificial structures.

  18. spib is required for primitive myeloid development in Xenopus.

    Science.gov (United States)

    Costa, Ricardo M B; Soto, Ximena; Chen, Yaoyao; Zorn, Aaron M; Amaya, Enrique

    2008-09-15

    Vertebrate blood formation occurs in 2 spatially and temporally distinct waves, so-called primitive and definitive hematopoiesis. Although definitive hematopoiesis has been extensively studied, the development of primitive myeloid blood has received far less attention. In Xenopus, primitive myeloid cells originate in the anterior ventral blood islands, the equivalent of the mammalian yolk sac, and migrate out to colonize the embryo. Using fluorescence time-lapse video microscopy, we recorded the migratory behavior of primitive myeloid cells from their birth. We show that these cells are the first blood cells to differentiate in the embryo and that they are efficiently recruited to embryonic wounds, well before the establishment of a functional vasculature. Furthermore, we isolated spib, an ETS transcription factor, specifically expressed in primitive myeloid precursors. Using spib antisense morpholino knockdown experiments, we show that spib is required for myeloid specification, and, in its absence, primitive myeloid cells retain hemangioblast-like characteristics and fail to migrate. Thus, we conclude that spib sits at the top of the known genetic hierarchy that leads to the specification of primitive myeloid cells in amphibians.

  19. Analysis of power and frequency control requirements in view of increased decentralized production and market liberalization

    International Nuclear Information System (INIS)

    Roffel, B.; Boer, W.W. de

    2003-01-01

    This paper presents a systematic approach of the analysis of the minimum control requirements that are imposed on power producing units in the Netherlands, especially in the case when decentralized production increases. Also some effects of the liberalization on the control behavior are analyzed. First an overview is given of the amount and type of power production in the Netherlands, followed by a review of the control requirements. Next models are described, including a simplified model for the UCTE power system. The model was tested against frequency and power measurements after failure of a 558 MW production unit in the Netherlands. Agreement between measurements and model predictions proved to be good. The model was subsequently used to analyze the primary and secondary control requirements and the impact of an increase in decentralized power production on the fault restoration capabilities of the power system. Since the latter production units are not actively participating in primary and secondary control, fault restoration takes longer and becomes unacceptable when only 35% of the power producing units participate in secondary control. Finally, the model was used to study the impact of deregulation, especially the effect of 'block scheduling', on additional control actions of the secondary control. (Author)

  20. Double impact of sterilizing pathogens: added value of increased life expectancy on pest control effectiveness.

    Science.gov (United States)

    Berec, Luděk; Maxin, Daniel

    2012-06-01

    Sterilizing pathogens are commonly assumed not to affect longevity of infected individuals, and if they do then negatively. Examples abound, however, of species in which the absence of reproduction actually increases life expectancy. This happens because by decreasing the energy outlay on reproduction individuals with lowered reproduction can live longer. Alternatively, fertile individuals are more susceptible to predators or parasitoids if the latter can capitalize on mating signals of the former. Here we develop and analyze an SI epidemiological model to explore whether and to what extent does such a life expectancy prolongation due to sterilizing pathogens affect host dynamics. In particular, we are interested in an added value of increased life expectancy on the possibility of successful pest control, that is, the effect of increased lifespan and hence increased potential of the infected individuals to spread the disease on pest control effectiveness. We show that although the parameter range in which we observe an effect of increased lifespan of the sterilized individuals is not large, the effect itself can be significant. In particular, the increase in pest control effectiveness can be very dramatic when disease transmission efficiency is close to birth rate, mortality rate of susceptibles is relatively high (i.e., the species is relatively short-lived), and sterilization efficiency is relatively high. Our results thus characterize pathogens that are promising candidates for an effective pest control and that might possibly be engineered if not occurring naturally.

  1. Increased all-cause mortality with psychotropic medication in Parkinson's disease and controls

    DEFF Research Database (Denmark)

    Frandsen, Rune; Baandrup, Lone; Kjellberg, Jakob

    2014-01-01

    AIM: Use of medication and polypharmacy is common as the population ages and its disease burden increases. We evaluated the association of antidepressants, benzodiazepines, antipsychotics and combinations of psychotropic drugs with all-cause mortality in patients with Parkinson's disease (PD...... of psychotropic medication in PD patients and controls. Hazard ratios were as follows for the medication types: selective serotonin reuptake inhibitors or serotonin-noradrenalin reuptake inhibitors, PD HR = 1.19, 95% CI = 1.04-1.36; Control HR = 1.77, 95% CI = 1.64-1.91; benzodiazepines, PD HR = 1.17, 95% CI = 0.......20-1.76; Control HR = 2.00, 95% CI 1.66-2.43; and combinations of these drugs compared with non-medicated PD patients and controls. Discontinuation of medication was associated with decreased mortality in both groups. CONCLUSIONS: The use of psychotropic medication in the elderly is associated with increased...

  2. Efficient Control of Energy Storage for Increasing the PV Hosting Capacity of LV Grids

    DEFF Research Database (Denmark)

    Hashemi Toghroljerdi, Seyedmostafa; Østergaard, Jacob

    2016-01-01

    grid is usually limited by overvoltage, and the efficient control of distributed electrical energy storage systems (EESSs) can considerably increase this capacity. In this paper, a new control approach based on the voltage sensitivity analysis is proposed to prevent overvoltage and increase the PV......Photovoltaic (PV) systems are among the renewable sources that electrical energy systems are adopting with increasing frequency. The majority of already-installed PV systems are decentralized units that are usually connected to lowvoltage (LV) distribution grids. The PV hosting capacity of an LV...... hosting capacity of LV grids by determining dynamic set points for EESS management. The method has the effectiveness of central control methods and can effectively decrease the energy storage required for overvoltage prevention, yet it eliminates the need for a broadband and fast communication. The net...

  3. CCAAT/enhancer binding protein a gene expression in Egyptian patients with acute myeloid leukemia

    International Nuclear Information System (INIS)

    Kassem, N.; Fahmy, A.; Desoky, M.; Zawam, H.M.; Medhat, N.; Medhat, N.

    2013-01-01

    Background: Transcription factors play a crucial role in myeloid differentiation and lineage determination. Tumor suppressor protein C/EBPa is a key regulator of granulocytic differentiation whose functional inactivation has become a pathophysiological signature of myeloid leukemia. Given the role that CCAAT/enhancer binding protein α (C/EBP α) plays in myelopoiesis, we anticipated that their expression might be disrupted in myeloid neoplasms. Purpose: To estimate the expression of C/EBP α mRNA in patients with acute myeloid leukemia and correlate its expression with the pathogenesis of the disease. Patients and methods: Forty AML patients and 20 age and sex matched healthy controls were included in the study. Blood samples of patients and controls were analyzed for CEBP α mRNA expression by quantitative RT-real time PCR using TaqMan technology and δδct method for calculation of gene expression. Results: Twenty-nine (72.5%) patients out of the 40 showed low expression levels of CEBP α mRNA below the cutoff value with median of 0.19 (range:0-0.87). While eleven (27.5%) patients out of the 40 showed higher expression levels of CEBP α above the cutoff value with median of 1.52 (range: 1.07-2). Seven patients out of the 11 showed higher expression levels of CEBP α mRNA belong to the M3 subtype of AML harboring the t(15;17) PML-RARa translocation. Conclusion: We conclude that the majority of the AML patients analyzed, express low levels of C/EBPa mRN. However, a subset of patients represented by the M3 subtype, express higher levels of C/EBPa

  4. Exploring the Potential for Increased Production from the Wave Energy Converter Lifesaver by Reactive Control

    Directory of Open Access Journals (Sweden)

    Marta Molinas

    2013-07-01

    Full Text Available Fred Olsen is currently testing their latest wave energy converter (WEC, Lifesaver, outside of Falmouth Bay in England, preparing it for commercial operation at the Wavehub test site. Previous studies, mostly focusing on hydrodynamics and peak to average power reduction, have shown that this device has potential for increased power extraction using reactive control. This article extends those analyses, adding a detailed model of the all-electric power take-off (PTO system, consisting of a permanent magnet synchronous generator, inverter and DC-link. Time domain simulations are performed to evaluate the PTO capabilities of the modeled WEC. However, when tuned towards reactive control, the generator losses become large, giving a very low overall system efficiency. Optimal control with respect to electrical output power is found to occur with low added mass, and when compared to pure passive loading, a 1% increase in annual energy production is estimated. The main factor reducing the effect of reactive control is found to be the minimum load-force constraint of the device. These results suggest that the Lifesaver has limited potential for increased production by reactive control. This analysis is nevertheless valuable, as it demonstrates how a wave-to-wire model can be used for investigation of PTO potential, annual energy production estimations and evaluations of different control techniques for a given WEC device.

  5. Interactions between default mode and control networks as a function of increasing cognitive reasoning complexity.

    Science.gov (United States)

    Hearne, Luke; Cocchi, Luca; Zalesky, Andrew; Mattingley, Jason B

    2015-07-01

    Successful performance of challenging cognitive tasks depends on a consistent functional segregation of activity within the default-mode network, on the one hand, and control networks encompassing frontoparietal and cingulo-opercular areas on the other. Recent work, however, has suggested that in some cognitive control contexts nodes within the default-mode and control networks may actually cooperate to achieve optimal task performance. Here, we used functional magnetic resonance imaging to examine whether the ability to relate variables while solving a cognitive reasoning problem involves transient increases in connectivity between default-mode and control regions. Participants performed a modified version of the classic Wason selection task, in which the number of variables to be related is systematically varied across trials. As expected, areas within the default-mode network showed a parametric deactivation with increases in relational complexity, compared with neural activity in null trials. Critically, some of these areas also showed enhanced connectivity with task-positive control regions. Specifically, task-based connectivity between the striatum and the angular gyri, and between the thalamus and right temporal pole, increased as a function of relational complexity. These findings challenge the notion that functional segregation between regions within default-mode and control networks invariably support cognitive task performance, and reveal previously unknown roles for the striatum and thalamus in managing network dynamics during cognitive reasoning. © 2015 Wiley Periodicals, Inc.

  6. Conservation of myeloid surface antigens on primate granulocytes.

    Science.gov (United States)

    Letvin, N L; Todd, R F; Palley, L S; Schlossman, S F; Griffin, J D

    1983-02-01

    Monoclonal antibodies reactive with myeloid cell surface antigens were used to study evolutionary changes in granulocyte surface antigens from primate species. Certain of these granulocyte membrane antigens are conserved in phylogenetically distant species, indicating the potential functional importance of these structures. The degree of conservation of these antigens reflects the phylogenetic relationship between primate species. Furthermore, species of the same genus show similar patterns of binding to this panel of anti-human myeloid antibodies. This finding of conserved granulocyte surface antigens suggests that non-human primates may provide a model system for exploring uses of monoclonal antibodies in the treatment of human myeloid disorders.

  7. Measures to increase the availability of electronic control units, illustrated by examples from power plant engineering

    International Nuclear Information System (INIS)

    Schmidt, R.

    1976-01-01

    The availibility of electric control units in the power plant engineering is increased by a decentralized construction, redundant current supply. miniaturized electronic modules, short-circuit-safe outputs, efficient protection of the wiring against over-voltage and intensive control of the afferent cables against wire break and short circuits. To reduce disturbing and damaging influences on the control multiple earthings should be avoided, the inductive coupling of distrubances should be reduced by parallel earth wires, and cable shields handled according to the prescriptions should reduce influences on the capacity. (orig.) [de

  8. A dual-motive model of scapegoating: displacing blame to reduce guilt or increase control.

    Science.gov (United States)

    Rothschild, Zachary K; Landau, Mark J; Sullivan, Daniel; Keefer, Lucas A

    2012-06-01

    The authors present a model that specifies 2 psychological motives underlying scapegoating, defined as attributing inordinate blame for a negative outcome to a target individual or group, (a) maintaining perceived personal moral value by minimizing feelings of guilt over one's responsibility for a negative outcome and (b) maintaining perceived personal control by obtaining a clear explanation for a negative outcome that otherwise seems inexplicable. Three studies supported hypotheses derived from this dual-motive model. Framing a negative outcome (environmental destruction or climate change) as caused by one's own harmful actions (value threat) or unknown sources (control threat) both increased scapegoating, and these effects occurred indirectly through feelings of guilt and perceived personal control, respectively (Study 1), and were differentially moderated by affirmations of moral value and personal control (Study 2). Also, scapegoating in response to value threat versus control threat produced divergent, theoretically specified effects on self-perceptions and behavioral intentions (Study 3). 2012 APA, all rights reserved

  9. Peptide Vaccination Against Cancer Testis Antigens in Combination With Azacitidine for Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia

    DEFF Research Database (Denmark)

    Holmberg, S.; Ortved Gang, A.; Svane, I.M.

    2016-01-01

    Myelodysplastic Syndrome (MDS) is a clonal disorder and characterized by increasing bone marrow failure due to accumulation of genetic and epigenetic changes in hematopoietic stem cells. Patients with high-risk disease have a poor prognosis and a high risk of progression to Acute Myeloid Leukemia...

  10. Impact Of Mutation-derived Antigens In Immune Recognition Of Hematological Malignancies, Specifically Myeloid Dysplastic Syndromes (MDS)

    DEFF Research Database (Denmark)

    Saini, Sunil Kumar; Dorfmüller, S.; Bjerregaard, Anne-Mette

    2016-01-01

    Mutation-derived neoepitopes have been suggested as a major component for immune recognition of solid tumors with a high mutational load, e.g. Melanoma and Non-Small-Cell Lung Cancer (NSCLC). Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by increasing...

  11. A Randomized Controlled Trial to Increase Navy Bean or Rice Bran Consumption in Colorectal Cancer Survivors.

    Science.gov (United States)

    Borresen, Erica C; Brown, Dustin G; Harbison, Greg; Taylor, Lynn; Fairbanks, Amanda; O'Malia, Joanne; Bazan, Marlon; Rao, Sangeeta; Bailey, Susan M; Wdowik, Melissa; Weir, Tiffany L; Brown, Regina J; Ryan, Elizabeth P

    2016-01-01

    Consumption of navy beans (NB) and rice bran (RB) have been shown to inhibit colon carcinogenesis. Given the overall poor diet quality in colorectal cancer (CRC) survivors and low reported intake of whole grains and legumes, practical strategies to increase consumption merit attention. This study determined feasibility of increasing NB or RB intake in CRC survivors to increase dietary fiber and examined serum inflammatory biomarkers and telomere lengths. Twenty-nine subjects completed a randomized controlled trial with foods that included cooked NB powder (35 g/day), heat-stabilized RB (30 g/day), or no additional ingredient. Fasting blood, food logs, and gastrointestinal health questionnaires were collected. The amount of NB or RB consumed equated to 4-9% of subjects' daily caloric intake and no major gastrointestinal issues were reported with increased consumption. Dietary fiber amounts increased in NB and RB groups at Weeks 2 and 4 compared to baseline and to control (P ≤ 0.01). Telomere length correlated with age and HDL cholesterol at baseline, and with improved serum amyloid A (SAA) levels at Week 4 (P ≤ 0.05). This study concludes feasibility of increased dietary NB and RB consumption to levels associated with CRC chemoprevention and warrants longer-term investigations with both foods in high-risk populations that include cancer prevention and control outcomes.

  12. Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia.

    Science.gov (United States)

    Tischkowitz, M D; Morgan, N V; Grimwade, D; Eddy, C; Ball, S; Vorechovsky, I; Langabeer, S; Stöger, R; Hodgson, S V; Mathew, C G

    2004-03-01

    Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (PFANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.

  13. Reduction of Myeloid-derived Suppressor Cells and Lymphoma Growth by a Natural Triterpenoid

    Science.gov (United States)

    Radwan, Faisal F. Y.; Hossain, Azim; God, Jason M.; Leaphart, Nathan; Elvington, Michelle; Nagarkatti, Mitzi; Tomlinson, Stephen; Haque, Azizul

    2016-01-01

    Lymphoma is a potentially life threatening disease. The goal of this study was to investigate the therapeutic potential of a natural triterpenoid, Ganoderic acid A (GA-A) in controlling lymphoma growth both in vitro and in vivo. Here, we show that GA-A treatment induces caspase-dependent apoptotic cell death characterized by a dose-dependent increase in active caspases 9 and 3, up-regulation of pro-apoptotic BIM and BAX proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA-A’s anti-growth activity, we show that lower doses of GA-A enhance HLA class II-mediated antigen presentation and CD4+ T cell recognition of lymphoma in vitro. The therapeutic relevance of GA-A treatment was also tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA-A-treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked down-regulation of STAT3 phosphorylation, reduction myeloid-derived suppressor cells (MDSCs), and enhancement of cytotoxic CD8+ T cells in the host. Thus, GA-A not only selectively induces apoptosis in lymphoma cells, but also enhances cell-mediated immune responses by attenuating MDSCs, and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA-A is a candidate for future drug design for the treatment of lymphoma. PMID:25142864

  14. A20 (Tnfaip3 deficiency in myeloid cells protects against influenza A virus infection.

    Directory of Open Access Journals (Sweden)

    Jonathan Maelfait

    Full Text Available The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-κB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections.

  15. The influence of artificially increased hip and trunk stiffness on balance control in man.

    NARCIS (Netherlands)

    Grüneberg, C.; Bloem, B.R.; Honegger, F.; Allum, J.H.J.

    2004-01-01

    Lightweight corsets were used to produce mid-body stiffening, rendering the hip and trunk joints practically inflexible. To examine the effect of this artificially increased stiffness on balance control, we perturbed the upright stance of young subjects (20-34 years of age) while they wore one of

  16. Using a Self-Control Training Procedure To Increase Appropriate Behavior.

    Science.gov (United States)

    Dixon, Mark R.; Hayes, Linda J.; Binder, Lisa M.; Manthey, Sharon; Sigman, Connie; Zdanowski, Darlene M.

    1998-01-01

    A study evaluated teaching a technique for self-control to three adults with developmental disabilities. Concurrent fixed-duration/progressive-duration reinforcement schedules were introduced in which both smaller and larger reinforcers were available immediately. When progressively increasing delays were introduced for the larger reinforcer,…

  17. Increase of Investment Appeal of Projects for Noise Control Measures in Urban Environment

    Science.gov (United States)

    Kolmakov, A. V.; Ignatyeva, V. O.

    2017-11-01

    The authors analyzed the contemporary noise pollution level in the large cities of the Russian Federation. The article identifies the factors causing the reduction of acoustically comfortable urban territories. It states the task for the increase of investment appeal of the projects aimed at noise control measures adoption.

  18. Increasing walking in patients with intermittent claudication: Protocol for a randomised controlled trial

    Directory of Open Access Journals (Sweden)

    O'Carroll Ronan E

    2010-10-01

    Full Text Available Abstract Background People with intermittent claudication are at increased risk of death from heart attack and stroke compared to matched controls. Surgery for intermittent claudication is for symptom management and does not reduce the risk of cardiovascular morbidity and mortality. Increasing physical activity can reduce claudication symptoms and may improve cardiovascular health. This paper presents the pilot study protocol for a randomised controlled trial to test whether a brief psychological intervention leads to increased physical activity, improvement in quality of life, and a reduction in the demand for surgery, for patients with intermittent claudication. Methods/Design We aim to recruit 60 patients newly diagnosed with intermittent claudication, who will be randomised into two groups. The control group will receive usual care, and the treatment group will receive usual care and a brief 2-session psychological intervention to modify illness and walking beliefs and develop a walking action plan. The primary outcome will be walking, measured by pedometer. Secondary outcomes will include quality of life and uptake of surgery for symptom management. Participants will be followed up after (a 4 months, (b 1 year and (c 2 years. Discussion This study will assess the acceptability and efficacy of a brief psychological intervention to increase walking in patients with intermittent claudication, both in terms of the initiation, and maintenance of behaviour change. This is a pilot study, and the results will inform the design of a larger multi-centre trial. Trial Registration Current Controlled Trials ISRCTN28051878

  19. Implications of the global increase of diabetes for tuberculosis control and patient care.

    NARCIS (Netherlands)

    Ruslami, R.; Aarnoutse, R.E.; Alisjahbana, B.; Ven, A.J.A.M. van der; Crevel, R. van

    2010-01-01

    OBJECTIVES: To review the current knowledge about tuberculosis (TB) and diabetes, assessing the implication of the global increase of diabetes for TB control and patient care. METHODS: Systematic literature review. RESULTS: Using public databases, it can be estimated that 12.6% (95% CI 9.2-17.3%) of

  20. Anti-Leukemic Activity of Shikonin: Role of ERP57 in Shikonin Induced Apoptosis in Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Rachana Trivedi

    2016-07-01

    Full Text Available Background/Aims: ER-Stress and activation of unfolded protein response belong to the major factors involved in chemoresistance in cancer cells. In this study we investigated the effect of shikonin on the survival of acute myeloid leukemia cells and the role of ER-stress protein ERP57, a protein disulfide isomerase, in improvement of chemotherapy. Methods: Using MTT assay we studied cytotoxic effects of shikonin on HL-60 cells. The flow cytometry was adopted to examine the shikonin induced mode of cell death in HL-60 cells. The overall protein expression alteration resulting from shikonin treatment was investigated using proteomics methods. Western blotting was performed to quantify the alteration in protein expression in HL-60 after shikonin treatment. Silencing and overexpression studies were carried out to highlight the therapeutic role of ERP57 in shikonin effect on AML cells. Results: Shikonin induces apoptosis in HL-60 cells without significant effect on Primary cells from healthy volunteers. The apoptotic effect was dose and time dependent and was accompanied by strong alteration in cell proteome. Among the proteins targeted by shikonin, ERP57 was significantly downregulated in HL-60 after treatment. Compared to healthy control ERP57 was found to be highly expressed in AML cell line HL60 and was downregulated after shikonin treatment. Overexpression of ERP57 protected HL-60 from shikonin induced apoptosis, whereas knockdown of ERP57 expression resulted in increase in shikonin induced apoptosis. Conclusions: Our results demonstrate that ERP57 plays a crucial role in resistance towards shikonin induced apoptosis in AML cells. Targeting of ERP57 might offer a new therapeutic option for the treatment of acute myeloid leukemia.

  1. Calreticulin Fragment 39-272 Promotes B16 Melanoma Malignancy through Myeloid-Derived Suppressor Cells In Vivo

    Directory of Open Access Journals (Sweden)

    Xiao-Yan He

    2017-10-01

    Full Text Available Calreticulin (CRT, a multifunctional Ca2+-binding glycoprotein mainly located in the endoplasmic reticulum, is a tumor-associated antigen that has been shown to play protective roles in angiogenesis suppression and anti-tumor immunity. We previously reported that soluble CRT (sCRT was functionally similar to heat shock proteins or damage-associated molecular patterns in terms of ability to activate myeloid cells and elicit strong inflammatory cytokine production. In the present study, B16 melanoma cell lines expressing recombinant CRT fragment 39-272 (sCRT/39-272 in secreted form (B16-CRT, or recombinant enhanced green fluorescence protein (rEGFP (B16-EGFP, were constructed for investigation on the roles of sCRT in tumor development. When s.c. inoculated into C57BL/6 mice, the B16-CRT cells were significantly more aggressive (in terms of solid tumor growth rate than B16-EGFP controls in a TLR4- and myeloid-derived suppressor cells (MDSC-dependent manner. The B16-CRT-bearing mice showed increased Gr1+ MDSC infiltration in tumor tissues, accelerated proliferation of CD11b+Ly6G+Ly6Clow (G-MDSC precursors in bone marrow, and higher percentages of G-MDSCs in spleen and blood, which was mirrored by decreased percentage of dendritic cells (DC in periphery. In in vitro studies, recombinant sCRT/39-272 was able to promote migration and survival of tumor-derived MDSCs via interaction with TLR4, inhibit MDSC differentiation into DC, and also elicit expression of inflammatory proteins S100A8 and S100A9 which are essential for functional maturation and chemotactic migration of MDSCs. Our data provide solid evidence for CRT as a double-edged sword in tumor development.

  2. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia.

    Science.gov (United States)

    Müller-Tidow, C; Tschanter, P; Röllig, C; Thiede, C; Koschmieder, A; Stelljes, M; Koschmieder, S; Dugas, M; Gerss, J; Butterfaß-Bahloul, T; Wagner, R; Eveslage, M; Thiem, U; Krause, S W; Kaiser, U; Kunzmann, V; Steffen, B; Noppeney, R; Herr, W; Baldus, C D; Schmitz, N; Götze, K; Reichle, A; Kaufmann, M; Neubauer, A; Schäfer-Eckart, K; Hänel, M; Peceny, R; Frickhofen, N; Kiehl, M; Giagounidis, A; Görner, M; Repp, R; Link, H; Kiani, A; Naumann, R; Brümmendorf, T H; Serve, H; Ehninger, G; Berdel, W E; Krug, U

    2016-03-01

    DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.

  3. Aversive emotional interference impacts behavior and prefronto-striatal activity during increasing attentional control.

    Science.gov (United States)

    Papazacharias, Apostolos; Taurisano, Paolo; Fazio, Leonardo; Gelao, Barbara; Di Giorgio, Annabella; Lo Bianco, Luciana; Quarto, Tiziana; Mancini, Marina; Porcelli, Annamaria; Romano, Raffaella; Caforio, Grazia; Todarello, Orlando; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

    2015-01-01

    Earlier studies have demonstrated that emotional stimulation modulates attentional processing during goal-directed behavior and related activity of a brain network including the inferior frontal gyrus (IFG) and the caudate nucleus. However, it is not clear how emotional interference modulates behavior and brain physiology during variation in attentional control, a relevant question for everyday life situations in which both emotional stimuli and cognitive load vary. The aim of this study was to investigate the impact of negative emotions on behavior and activity in IFG and caudate nucleus during increasing levels of attentional control. Twenty two healthy subjects underwent event-related functional magnetic resonance imaging while performing a task in which neutral or fearful facial expressions were displayed before stimuli eliciting increasing levels of attentional control processing. Results indicated slower reaction time (RT) and greater right IFG activity when fearful compared with neutral facial expressions preceded the low level of attentional control. On the other hand, fearful facial expressions preceding the intermediate level of attentional control elicited faster behavioral responses and greater activity in the right and left sides of the caudate. Finally, correlation analysis indicated a relationship between behavioral correlates of attentional control after emotional interference and right IFG activity. All together, these results suggest that the impact of negative emotions on attentional processing is differentially elicited at the behavioral and physiological levels as a function of cognitive load.

  4. Emerging therapies for acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Caner Saygin

    2017-04-01

    Full Text Available Abstract Acute myeloid leukemia (AML is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH inhibitors, vadastuximab or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin, epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC inhibitors, bromodomain and extraterminal (BET inhibitors, FMS-like tyrosine kinase receptor 3 (FLT3 inhibitors, and antibody-drug conjugates (vadastuximab, as well as cell cycle inhibitors (volasertib, B-cell lymphoma 2 (BCL-2 inhibitors, and aminopeptidase inhibitors. These agents are actively undergoing clinical investigation alone or in combination with available chemotherapy.

  5. Safety margins in older adults increase with improved control of a dynamic object

    Science.gov (United States)

    Hasson, Christopher J.; Sternad, Dagmar

    2014-01-01

    Older adults face decreasing motor capabilities due to pervasive neuromuscular degradations. As a consequence, errors in movement control increase. Thus, older individuals should maintain larger safety margins than younger adults. While this has been shown for object manipulation tasks, several reports on whole-body activities, such as posture and locomotion, demonstrate age-related reductions in safety margins. This is despite increased costs for control errors, such as a fall. We posit that this paradox could be explained by the dynamic challenge presented by the body or also an external object, and that age-related reductions in safety margins are in part due to a decreased ability to control dynamics. To test this conjecture we used a virtual ball-in-cup task that had challenging dynamics, yet afforded an explicit rendering of the physics and safety margin. The hypotheses were: (1) When manipulating an object with challenging dynamics, older adults have smaller safety margins than younger adults. (2) Older adults increase their safety margins with practice. Nine young and 10 healthy older adults practiced moving the virtual ball-in-cup to a target location in exactly 2 s. The accuracy and precision of the timing error quantified skill, and the ball energy relative to an escape threshold quantified the safety margin. Compared to the young adults, older adults had increased timing errors, greater variability, and decreased safety margins. With practice, both young and older adults improved their ability to control the object with decreased timing errors and variability, and increased their safety margins. These results suggest that safety margins are related to the ability to control dynamics, and may explain why in tasks with simple dynamics older adults use adequate safety margins, but in more complex tasks, safety margins may be inadequate. Further, the results indicate that task-specific training may improve safety margins in older adults. PMID:25071566

  6. Safety Margins in Older Adults Increase with Improved Control of a Dynamic Object

    Directory of Open Access Journals (Sweden)

    Christopher James Hasson

    2014-07-01

    Full Text Available Older adults face decreasing motor capabilities due to pervasive neuromuscular degradations. As a consequence errors in movement control increase. Thus, older individuals should maintain larger safety margins than younger adults. While this has been shown for object manipulation tasks, several reports on whole-body activities, such as posture and locomotion, however demonstrate age-related reductions in safety margins. This is despite increased costs for control errors, such as a fall. We posit that this paradox could be explained by the dynamic challenge presented by the body or an external object, and that age-related reductions in safety margins are in part due to a decreased ability to control dynamics. To test this conjecture we used a virtual ball-in-cup task that had challenging dynamics, yet afforded an explicit rendering of the physics and safety margin. The hypotheses were: 1 When manipulating an object with challenging dynamics, older adults have smaller safety margins than younger adults. 2 Older adults increase their safety margins with practice. Nine young and 10 healthy older adults practiced moving the virtual ball-in-cup to a target location in exactly two seconds. The accuracy and precision of the timing error quantified skill and the ball energy relative to an escape threshold quantified the safety margin. Compared to the young adults, older adults had increased timing errors, greater variability, and decreased safety margins. With practice, both young and older adults improved their ability to control the object with decreased timing errors and variability, and increased their safety margins. These results suggest that safety margins are related to the ability to control dynamics, and may explain why in tasks with simple dynamics older adults use adequate safety margins, but in more complex tasks, safety margins may be inadequate. Further, the results indicate that task-specific training may improve safety margins in older

  7. JAK and MPL mutations in myeloid malignancies.

    Science.gov (United States)

    Tefferi, Ayalew

    2008-03-01

    The Janus family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3 and tyrosine kinase 2) transduces signals downstream of type I and II cytokine receptors via signal transducers and activators of transcription (STATs). JAK3 is important in lymphoid and JAK2 in myeloid cell proliferation and differentiation. The thrombopoietin receptor MPL is one of several JAK2 cognate receptors and is essential for myelopoiesis in general and megakaryopoiesis in particular. Germline loss-of-function (LOF) JAK3 and MPL mutations cause severe combined immunodeficiency and congenital amegakaryocytic thrombocytopenia, respectively. Germline gain-of-function (GOF) MPL mutation (MPLS505N) causes familial thrombocytosis. Somatic JAK3 (e.g. JAK3A572V, JAK3V722I, JAK3P132T) and fusion JAK2 (e.g. ETV6-JAK2, PCM1-JAK2, BCR-JAK2) mutations have respectively been described in acute megakaryocytic leukemia and acute leukemia/chronic myeloid malignancies. However, current attention is focused on JAK2 (e.g. JAK2V617F, JAK2 exon 12 mutations) and MPL (e.g. MPLW515L/K/S, MPLS505N) mutations associated with myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2V617F, is invariably associated with polycythemia vera (PV). The latter mutation also occurs in the majority of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). MPL mutational frequency in MPNs is substantially less (<10%). In general, despite a certain degree of genotype - phenotype correlations, the prognostic relevance of harbouring one of these mutations, or their allele burden when present, remains dubious. Regardless, based on the logical assumption that amplified JAK-STAT signalling is central to the pathogenesis of PV, ET and PMF, several anti-JAK2 tyrosine kinase inhibitors have been developed and are currently being tested in humans with these disorders.

  8. To increase controllability of a large flexible antenna by modal optimization

    Science.gov (United States)

    Wang, Feng; Wang, Pengpeng; Jiang, Wenjian

    2017-12-01

    Large deployable antennas are widely used in aerospace engineering to meet the envelop limit of rocket fairing. The high flexibility and low damping of antenna has proposed critical requirement not only for stability control of the antenna itself, but also for attitude control of the satellite. This paper aims to increase controllability of a large flexible antenna by modal optimization. Firstly, Sensitivity analysis of antenna modal frequencies to stiffness of support structure and stiffness of scanning mechanism are conducted respectively. Secondly, Modal simulation results of antenna frequencies are given, influences of scanning angles on moment of inertia and modal frequencies are evaluated, and modal test is carried out to validate the simulation results. All the simulation and test results show that, after modal optimization the modal characteristic of the large deployable antenna meets the controllability requirement well.

  9. Adult Acute Myeloid Leukemia Treatment (PDQ®)—Patient Version

    Science.gov (United States)

    Treatment options for adult acute myeloid leukemia (AML) include chemotherapy, radiation therapy, stem cell transplant, and other medications. Get detailed information about the treatment of new and recurrent AML in this expert-reviewed summary.

  10. Endometrial and acute myeloid leukemia cancer genomes characterized

    Science.gov (United States)

    Two studies from The Cancer Genome Atlas (TCGA) program reveal details about the genomic landscapes of acute myeloid leukemia (AML) and endometrial cancer. Both provide new insights into the molecular underpinnings of these cancers.

  11. Genetics of therapy-related myelodysplasia and acute myeloid leukemia

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, J.; Andersen, Mette Klarskov; Andersen, M.T.

    2008-01-01

    Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according...

  12. Myeloid sarcoma of the rib: An atypical isolated chest finding

    Directory of Open Access Journals (Sweden)

    Antonio Raucci

    2015-03-01

    Systemic treatment was administered and currently neither systemic nor local relapse has been identified. Our experience suggests surgical resection could be a valid treatment in isolated myeloid sarcoma patients.

  13. Automatic control of negative emotions: evidence that structured practice increases the efficiency of emotion regulation.

    Science.gov (United States)

    Christou-Champi, Spyros; Farrow, Tom F D; Webb, Thomas L

    2015-01-01

    Emotion regulation (ER) is vital to everyday functioning. However, the effortful nature of many forms of ER may lead to regulation being inefficient and potentially ineffective. The present research examined whether structured practice could increase the efficiency of ER. During three training sessions, comprising a total of 150 training trials, participants were presented with negatively valenced images and asked either to "attend" (control condition) or "reappraise" (ER condition). A further group of participants did not participate in training but only completed follow-up measures. Practice increased the efficiency of ER as indexed by decreased time required to regulate emotions and increased heart rate variability (HRV). Furthermore, participants in the ER condition spontaneously regulated their negative emotions two weeks later and reported being more habitual in their use of ER. These findings indicate that structured practice can facilitate the automatic control of negative emotions and that these effects persist beyond training.

  14. Increased expression of TLR9 associated with pro-inflammatory S100A8 and IL-8 in diabetic wounds could lead to unresolved inflammation in type 2 diabetes mellitus (T2DM) cases with impaired wound healing.

    Science.gov (United States)

    Singh, Kanhaiya; Agrawal, Neeraj K; Gupta, Sanjeev K; Sinha, Pratima; Singh, Kiran

    2016-01-01

    Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which causes a chain of abrupt biochemical and physiological changes. Immune dys-regulation is the hallmark of T2DM that could contribute to prolonged inflammation causing transformation of wounds into non-healing chronic ulcers. Toll like receptor -9 (TLR9) is a major receptor involved in innate immune regulation. TLR9 activation induces release of pro-inflammatory molecules like S100A8 and interleukin-8 (IL-8) by myeloid cells causing migration of myeloid cells to the site of inflammation. We hypothesized that pro-inflammatory S100A8 and IL-8 proteins could cause persistent inflammation in chronic wounds like diabetic foot ulcer (DFU) and may contribute to impaired wound healing in T2DM patients. Expression of TLR9 and its downstream effector molecules S100A8, and IL-8 were analyzed in chronic diabetic wound and non-diabetic control wound tissue samples by semiquantitative reverse transcriptase - polymerase chain reaction (RT-PCR), quantitative RT-PCR, western blot and immunofluorescence. CD11b(+)CD33(+) myeloid cells were analyzed by flow cytometry. TLR9 message and protein were higher in diabetic wounds compared to control wounds (p=0.03, t=2.21 for TLR9 mRNA; p=diabetic wounds (p=0.003, t=3.1 for S100A8 mRNA; p=0.04, t=2.04 for IL-8). CD11b(+) CD33(+) myeloid cells were decreased in T2DM as compared to non-diabetic controls (p=0.001, t=3.6). DFU subjects had higher levels of CD11b(+) CD33(+) myeloid cells as compared to non-DFU T2DM control (p=0.003, t=2.8). Infection in the wound microenvironment could be the cause of increase in CD11b(+)CD33(+) myeloid cells in DFU (p=0.03, t=2.5). The up-regulation of myeloid cell-derived pro-inflammatory molecules S100A8 and IL-8 in combination with lower levels of CD11b(+) CD33(+) myeloid cells may cause the impairment of wound healing in T2DM subjects leading to chronic ulcers. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. The Effectiveness of Teaching Intervention Internal Locus of Control on Increasing Marital Adjustment and Satisfaction

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    Askari Asghari-Ganji

    2015-03-01

    Full Text Available Background and purpose: Satisfaction with marital life is the most important issue in the joint life, which has the greatest effect on durability and failure of couple’s lives. Based on this, the main goal of the present research is to study the effectiveness of teaching intervention based on internal locus of control in increasing marital adjustment and satisfaction has been investigated. Materials and Methods: The research design was pre- and post-test with control group. Statistical population of this research includes 100 married students of Farhangian University of Babol, Iran. To determine the sample, initially 100 questionnaires of Rotter’s locus of control and Spanier’s marital adjustment were distributed among the married students. Among this population, 42 couples both had external locus of control and suffered marital maladjustment, 20 couples were selected by simple randomized method and were placed into two experimental and control groups, such that 10 couples were placed in the experimental group and 10 couples were placed in control group. Data were analyzed using the independent t-test method. Results: Research results showed that, since effectiveness of training communicational skills based on internal locus of control on increasing marital attachment of couples was calculated t-value (t = 6.04 and (t= 4.71 for women and men, respectively with degree of freedom of 19 is bigger than t-value in the table (t = 2.53 therefore, null hypothesis is rejected and with confidence degree of 99%. Conclusion: Teaching intervention based on internal control can be used as one of the intervention models for couples who suffer from marital dissatisfaction and think of divorce.

  16. Is an increase of MRSA in Oslo, Norway, associated with changed infection control policy?

    Science.gov (United States)

    Andersen, Bjørg Marit; Rasch, Mette; Syversen, Gaute

    2007-12-01

    The objective was to describe the prevalence of MRSA in Oslo, Norway, before and after introduction of a new National MRSA Control Guideline. From 1993 to 2006, we prospectively collected clinical and microbiological data on all MRSA cases in Oslo, Norway. Two MRSA guidelines; a strict Ullevål Standard MRSA Guideline and a less strict National MRSA Control Guideline were compared. During 1993-2006, 358 MRSA cases were registered in Oslo; 43.9% detected in Ullevål University Hospital, 21.2% in nursing homes, and 18.7% in primary healthcare. One out of three (30.4%) were import-associated, and one out of ten (11.2%) were healthcare personnel. From 2004 on, a new National MRSA Control Guideline was introduced in primary healthcare, served by the community infection control. From 2004 on, there was a 4-6-fold increase of MRSA in primary healthcare (p = 0.038) and nursing homes (p = 0.005). Increase of MRSA cases at Ullevål (p Norway may be associated with the 4-6-fold increase of MRSA cases in the community after 2003.

  17. Characterization of miRNomes in Acute and Chronic Myeloid

    Directory of Open Access Journals (Sweden)

    Qian Xiong

    2014-04-01

    Full Text Available Myeloid leukemias are highly diverse diseases and have been shown to be associated with microRNA (miRNA expression aberrations. The present study involved an in-depth miRNome analysis of two human acute myeloid leukemia (AML cell lines, HL-60 and THP-1, and one human chronic myeloid leukemia (CML cell line, K562, via massively parallel signature sequencing. mRNA expression profiles of these cell lines that were established previously in our lab facilitated an integrative analysis of miRNA and mRNA expression patterns. miRNA expression profiling followed by differential expression analysis and target prediction suggested numerous miRNA signatures in AML and CML cell lines. Some miRNAs may act as either tumor suppressors or oncomiRs in AML and CML by targeting key genes in AML and CML pathways. Expression patterns of cell type-specific miRNAs could partially reflect the characteristics of K562, HL-60 and THP-1 cell lines, such as actin filament-based processes, responsiveness to stimulus and phagocytic activity. miRNAs may also regulate myeloid differentiation, since they usually suppress differentiation regulators. Our study provides a resource to further investigate the employment of miRNAs in human leukemia subtyping, leukemogenesis and myeloid development. In addition, the distinctive miRNA signatures may be potential candidates for the clinical diagnosis, prognosis and treatment of myeloid leukemias.

  18. Strategy for increasing the participation of masyarakat peduli api in forest fire control

    Science.gov (United States)

    Ni’mah, N. L. K.; Herdiansyah, H.; Soesilo, T. E. B.; Mutia, E. F.

    2018-03-01

    Forest fires have negative impact on ecology, health, and damage economic activities. One of conservation areas facing the threat of forest fire is Gunung Ciremai National Park. This research aims to formulate a strategy to increase the participation of Masyarakat Peduli Api in the effort of forest fire control. This research use quantitative method with SWOT analysis. Expert consisting of representatives from the national park, Ministry of Environment and Forestry, and BPBD Kuningan Regency. An alternative strategy based on SWOT analysis is in quadrant 1 with coordinate point (0,39; 1,23). The position shows that sustainability of national park management through forest fire control can be done with an aggressive strategy. That is maximizing the strength that is owned with its potential as an ecotourism area to increase community motivation to engage in forest fire control activities. Provision of tourism management licenses will create employment opportunities and increase income for the community so it is expected to increase community participation to prevent the occurrence of forest fires rather than forest fire prevention.

  19. Treatments for chronic myeloid leukemia: a qualitative systematic review

    Directory of Open Access Journals (Sweden)

    Ferdin

    2012-08-01

    Full Text Available Roxanne Ferdinand,1 Stephen A Mitchell,2 Sarah Batson,2 Indra Tumur11Pfizer, Tadworth, UK; 2Abacus International, Bicester, UKBackground: Chronic myeloid leukemia (CML is a myeloproliferative disorder of blood stem cells. The tyrosine kinase inhibitor (TKI imatinib was the first targeted therapy licensed for patients with chronic-phase CML, and its introduction was associated with substantial improvements in response and survival compared with previous therapies. Clinical trial data are now available for the second-generation TKIs (nilotinib, dasatinib, and bosutinib in the first-, second-, and third-line settings. A qualitative systematic review was conducted to qualitatively compare the clinical effectiveness, safety, and effect on quality of life of TKIs for the management of chronic-, accelerated-, or blast-phase CML patients.Methods: Included studies were identified through a search of electronic databases in September 2011, relevant conference proceedings and the grey literature.Results: In the first-line setting, the long-term efficacy (up to 8 years of imatinib has been confirmed in a single randomized controlled trial (International Randomized Study of Interferon [IRIS]. All second-generation TKIs reported lower rates of transformation, and comparable or superior complete cytogenetic response (CCyR, major molecular response (MMR, and complete molecular response rates compared with imatinib by 2-year follow-up. Each of the second-generation TKIs was associated with a distinct adverse-event profile. Bosutinib was the only second-generation TKI to report quality-of-life data (no significant difference compared with imatinib treatment. Data in the second- and third-line setting confirmed the efficacy of the second-generation TKIs in either imatinib-resistant or -intolerant patients, as measured by CCyR and MMR rates.Conclusion: Data from first-line randomized controlled trials reporting up to 2-year follow-up indicate superior response

  20. Mutations in TET2 and DNMT3A genes are associated with changes in global and gene-specific methylation in acute myeloid leukemia.

    Science.gov (United States)

    Ponciano-Gómez, Alberto; Martínez-Tovar, Adolfo; Vela-Ojeda, Jorge; Olarte-Carrillo, Irma; Centeno-Cruz, Federico; Garrido, Efraín

    2017-10-01

    Acute myeloid leukemia is characterized by its high biological and clinical heterogeneity, which represents an important barrier for a precise disease classification and accurate therapy. While epigenetic aberrations play a pivotal role in acute myeloid leukemia pathophysiology, molecular signatures such as change in the DNA methylation patterns and genetic mutations in enzymes needed to the methylation process can also be helpful for classifying acute myeloid leukemia. Our study aims to unveil the relevance of DNMT3A and TET2 genes in global and specific methylation patterns in acute myeloid leukemia. Peripheral blood samples from 110 untreated patients with acute myeloid leukemia and 15 healthy control individuals were collected. Global 5-methylcytosine and 5-hydroxymethylcytosine in genomic DNA from peripheral blood leukocytes were measured by using the MethylFlashTM Quantification kits. DNMT3A and TET2 expression levels were evaluated by real-time quantitative polymerase chain reaction. The R882A hotspot of DNMT3A and exons 6-10 of TET2 were amplified by polymerase chain reaction and sequenced using the Sanger method. Methylation patterns of 16 gene promoters were evaluated by pyrosequencing after treating DNA with sodium bisulfite, and their transcriptional products were measured by real-time quantitative polymerase chain reaction.Here, we demonstrate altered levels of 5-methylcytosine and 5-hydroxymethylcytosine and highly variable transcript levels of DNMT3A and TET2 in peripheral blood leukocytes from acute myeloid leukemia patients. We found a mutation prevalence of 2.7% for DNMT3A and 11.8% for TET2 in the Mexican population with this disease. The average overall survival of acute myeloid leukemia patients with DNMT3A mutations was only 4 months. In addition, we showed that mutations in DNMT3A and TET2 may cause irregular DNA methylation patterns and transcriptional expression levels in 16 genes known to be involved in acute myeloid leukemia pathogenesis

  1. Mutations in Epigenetic Modifiers in Myeloid Malignancies and the Prospect of Novel Epigenetic-Targeted Therapy

    Directory of Open Access Journals (Sweden)

    Amir T. Fathi

    2012-01-01

    Full Text Available In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs, myeloproliferative neoplasms (MPNs, and acute myeloid leukemia (AML. Among these alterations have been mutations in genes, such as IDH1/2, TET2, DNMT3A, and EZH2, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors.

  2. Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice.

    Directory of Open Access Journals (Sweden)

    Iraklis C Kourtis

    Full Text Available Nanoparticles have been extensively developed for therapeutic and diagnostic applications. While the focus of nanoparticle trafficking in vivo has traditionally been on drug delivery and organ-level biodistribution and clearance, recent work in cancer biology and infectious disease suggests that targeting different cells within a given organ can substantially affect the quality of the immunological response. Here, we examine the cell-level biodistribution kinetics after administering ultrasmall Pluronic-stabilized poly(propylene sulfide nanoparticles in the mouse. These nanoparticles depend on lymphatic drainage to reach the lymph nodes and blood, and then enter the spleen rather than the liver, where they interact with monocytes, macrophages and myeloid dendritic cells. They were more readily taken up into lymphatics after intradermal (i.d. compared to intramuscular administration, leading to ∼50% increased bioavailability in blood. When administered i.d., their distribution favored antigen-presenting cells, with especially strong targeting to myeloid cells. In tumor-bearing mice, the monocytic and the polymorphonuclear myeloid-derived suppressor cell compartments were efficiently and preferentially targeted, rendering this nanoparticulate formulation potentially useful for reversing the highly suppressive activity of these cells in the tumor stroma.

  3. Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice.

    Science.gov (United States)

    Kourtis, Iraklis C; Hirosue, Sachiko; de Titta, Alexandre; Kontos, Stephan; Stegmann, Toon; Hubbell, Jeffrey A; Swartz, Melody A

    2013-01-01

    Nanoparticles have been extensively developed for therapeutic and diagnostic applications. While the focus of nanoparticle trafficking in vivo has traditionally been on drug delivery and organ-level biodistribution and clearance, recent work in cancer biology and infectious disease suggests that targeting different cells within a given organ can substantially affect the quality of the immunological response. Here, we examine the cell-level biodistribution kinetics after administering ultrasmall Pluronic-stabilized poly(propylene sulfide) nanoparticles in the mouse. These nanoparticles depend on lymphatic drainage to reach the lymph nodes and blood, and then enter the spleen rather than the liver, where they interact with monocytes, macrophages and myeloid dendritic cells. They were more readily taken up into lymphatics after intradermal (i.d.) compared to intramuscular administration, leading to ∼50% increased bioavailability in blood. When administered i.d., their distribution favored antigen-presenting cells, with especially strong targeting to myeloid cells. In tumor-bearing mice, the monocytic and the polymorphonuclear myeloid-derived suppressor cell compartments were efficiently and preferentially targeted, rendering this nanoparticulate formulation potentially useful for reversing the highly suppressive activity of these cells in the tumor stroma.

  4. Affectionless control by the same-sex parents increases dysfunctional attitudes about achievement.

    Science.gov (United States)

    Otani, Koichi; Suzuki, Akihito; Matsumoto, Yoshihiko; Sadahiro, Ryoichi; Enokido, Masanori

    2014-08-01

    The affectionless control parenting has been associated with depression in recipients. The aim of this study was to examine the effect of this parenting style on dysfunctional attitudes predisposing to depression. The subjects were 666 Japanese volunteers. Perceived parental rearing was evaluated by the Parental Bonding Instrument, which has the care and protection subscales. Parental rearing was classified into four types, i.e., optimal parenting (high care/low protection), affectionate constraint (high care/high protection), neglectful parenting (low care/low protection), and affectionless control (low care/high protection). Dysfunctional attitudes were evaluated by the 24-item Dysfunctional Attitude Scale, which has the achievement, dependency and self-control subscales. Males with paternal affectionless control had higher achievement scores than those with paternal optimal parenting (P=.016). Similarly, females with maternal affectionless control had higher achievement scores than those with maternal optimal parenting (P=.016). The present study suggests that affectionless control by the same-sex parents increases dysfunctional attitudes about achievement. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Vestibular control of standing balance is enhanced with increased cognitive load.

    Science.gov (United States)

    McGeehan, Michael A; Woollacott, Marjorie H; Dalton, Brian H

    2017-04-01

    When cognitive load is elevated during a motor task, cortical inhibition and reaction time are increased; yet, standing balance control is often unchanged. This disconnect is likely explained by compensatory mechanisms within the balance system such as increased sensitivity of the vestibulomotor pathway. This study aimed to determine the effects of increased cognitive load on the vestibular control of standing balance. Participants stood blindfolded on a force plate with their head facing left and arms relaxed at their sides for two trials while exposed to continuous electrical vestibular stimulation (EVS). Participants either stood quietly or executed a cognitive task (double-digit arithmetic). Surface electromyography (EMG) and anterior-posterior ground-body forces (APF) were measured in order to evaluate vestibular-evoked balance responses in the frequency (coherence and gain) and time (cumulant density) domains. Total distance traveled for anterior-posterior center of pressure (COP) was assessed as a metric of balance variability. Despite similar distances traveled for COP, EVS-medial gastrocnemius (MG) EMG and EVS-APF coherence and EVS-TA EMG and EVS-MG EMG gain were elevated for multiple frequencies when standing with increased cognitive load. For the time domain, medium-latency peak amplitudes increased by 13-54% for EVS-APF and EVS-EMG relationships with the cognitive task compared to without. Peak short-latency amplitudes were unchanged. These results indicate that reliance on vestibular control of balance is enhanced when cognitive load is elevated. This augmented neural strategy may act to supplement divided cortical processing resources within the balance system and compensate for the acute neuromuscular modifications associated with increased cognitive demand.

  6. Alloreactive natural killer cells for the treatment of acute myeloid leukemia: from stem cell transplantation to adoptive immunotherapy

    Directory of Open Access Journals (Sweden)

    Loredana eRuggeri

    2015-10-01

    Full Text Available Natural killer cells express activating and inhibitory receptors which recognize MHC class I alleles, termed Killer cell Immunoglobulin-like Receptors (KIRs. Preclinical and clinical data from haploidentical T-cell depleted stem cell transplantation have demonstrated that alloreactive KIR-L mismatched natural killer cells play a major role as effectors against acute myeloid leukemia. Outside the transplantation setting, several reports have proven the safety and feasibility of natural killer cell infusion in acute myeloid leukemia patients and, in some cases, provided evidence that transferred NK cells are functionally alloreactive and may have a role in disease control. Aim of the present work is to briefly summarize the most recent advances in the field by moving from the first preclinical and clinical demonstration of donor NK alloreactivity in the transplantation setting to the most recent attempts of exploiting the use of alloreactive NK cell infusion as a means of adoptive immunotherapy against acute myeloid leukemia. Altogether, these data highlight the pivotal role of NK cells for the development of novel immunological approaches in the clinical management of acute myeloid leukemia.

  7. Control of root system architecture by DEEPER ROOTING 1 increases rice yield under drought conditions.

    Science.gov (United States)

    Uga, Yusaku; Sugimoto, Kazuhiko; Ogawa, Satoshi; Rane, Jagadish; Ishitani, Manabu; Hara, Naho; Kitomi, Yuka; Inukai, Yoshiaki; Ono, Kazuko; Kanno, Noriko; Inoue, Haruhiko; Takehisa, Hinako; Motoyama, Ritsuko; Nagamura, Yoshiaki; Wu, Jianzhong; Matsumoto, Takashi; Takai, Toshiyuki; Okuno, Kazutoshi; Yano, Masahiro

    2013-09-01

    The genetic improvement of drought resistance is essential for stable and adequate crop production in drought-prone areas. Here we demonstrate that alteration of root system architecture improves drought avoidance through the cloning and characterization of DEEPER ROOTING 1 (DRO1), a rice quantitative trait locus controlling root growth angle. DRO1 is negatively regulated by auxin and is involved in cell elongation in the root tip that causes asymmetric root growth and downward bending of the root in response to gravity. Higher expression of DRO1 increases the root growth angle, whereby roots grow in a more downward direction. Introducing DRO1 into a shallow-rooting rice cultivar by backcrossing enabled the resulting line to avoid drought by increasing deep rooting, which maintained high yield performance under drought conditions relative to the recipient cultivar. Our experiments suggest that control of root system architecture will contribute to drought avoidance in crops.

  8. Randomized Controlled Trial of Social Media: Effect of Increased Intensity of the Intervention.

    Science.gov (United States)

    Fox, Caroline S; Gurary, Ellen B; Ryan, John; Bonaca, Marc; Barry, Karen; Loscalzo, Joseph; Massaro, Joseph

    2016-04-27

    A prior randomized controlled trial of social media exposure at Circulation determined that social media did not increase 30-day page views. Whether insufficient social media intensity contributed to these results is uncertain. Original article manuscripts were randomized to social media exposure compared with no social media exposure (control) at Circulation beginning in January 2015. Social media exposure consisted of Facebook and Twitter posts on the journal's accounts. To increase social media intensity, a larger base of followers was built using advertising and organic growth, and posts were presented in triplicate and boosted on Facebook and retweeted on Twitter. The primary outcome was 30-day page views. Stopping rules were established at the point that 50% of the manuscripts were randomized and had 30-day follow-up to compare groups on 30-day page views. The trial was stopped for futility on September 26, 2015. Overall, 74 manuscripts were randomized to receive social media exposure, and 78 manuscripts were randomized to the control arm. The intervention and control arms were similar based on article type (P=0.85), geographic location of the corresponding author (P=0.33), and whether the manuscript had an editorial (P=0.80). Median number of 30-day page views was 499.5 in the social media arm and 450.5 in the control arm; there was no evidence of a treatment effect (P=0.38). There were no statistically significant interactions of treatment by manuscript type (P=0.86), by corresponding author (P=0.35), by trimester of publication date (P=0.34), or by editorial status (P=0.79). A more intensive social media strategy did not result in increased 30-day page views of original research. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  9. Efficient Control of Active Transformers for Increasing the PV Hosting Capacity of LV Grids

    DEFF Research Database (Denmark)

    Hashemi Toghroljerdi, Seyedmostafa; Østergaard, Jacob; Degner, Thomas

    2016-01-01

    . The potential interferences between the operation of active transformers and the reactive power absorption by PV inverters are investigated, and a voltage droop control approach is proposed for the efficient control of these transformers during high PV generation periods. The proposed method can potentially...... increase the PV hosting capacity of the grid, while eliminating the need for a complex and centralized controller. The voltages of specific locations or the grid state estimations provide adequate data for adjustments of the droop parameters. The simulations and field test results associated...... with the implementation of the proposed method to a newly developed active LV grid with high PV penetration in Felsberg, Germany, confirm the efficiency of the proposed method....

  10. Inhomogeneous dose escalation increases expected local control for NSCLC patients with lymph node involvement without increased mean lung dose

    DEFF Research Database (Denmark)

    Nielsen, Tine B; Hansen, Olfred; Schytte, Tine

    2014-01-01

    in mediastinum, and the thorax wall. The dose was escalated using a TCP model implemented into the planning system. The difference in TCP values between the homogeneous and inhomogeneous plans were evaluated using two different TCP models. RESULTS: Dose escalation was possible for all patients. TCP values based...... to the mediastinum were observed: 2.5 Gy for aorta, 4.4 Gy for the connective tissue, 1.6 Gy for the heart, and 2.6 Gy for trachea + bronchi. CONCLUSION: Increased target doses and TCP values using inhomogeneous dose distributions could be achieved for all patients, regardless of lymph node involvement, tumour stage...

  11. Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia

    International Nuclear Information System (INIS)

    Cerveira, Nuno; Snijder, Simone; Mariz, José M; Norton, Lucília; Mellink, Clemens H; Buijs, Arjan; Teixeira, Manuel R; Santos, Joana; Bizarro, Susana; Costa, Vera; Ribeiro, Franclim R; Lisboa, Susana; Correia, Cecília; Torres, Lurdes; Vieira, Joana

    2009-01-01

    A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in MLL-related leukemia. Recently, we have established the MLL-SEPT2 gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified MLL and SEPT2 gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of MLL-SEPT2-associated myeloid neoplasms so far described in the literature. Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: CBFB-MYH11 (n = 13), PML-RARA (n = 12); RUNX1-RUNX1T1 (n = 12), normal karyotype (n = 11), and MLL gene fusions other than MLL-SEPT2 (n = 10). We also studied all three MLL-SEPT2 myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient. When compared with normal controls, we found a 12.8-fold reduction of wild-type SEPT2 and MLL-SEPT2 combined expression in cases with the MLL-SEPT2 gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type MLL and MLL-SEPT2 combined expression (p = 0.028). The down-regulation of SEPT2 in MLL-SEPT2 myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other MLL gene fusions). In addition, MLL expression was also down-regulated in the group of MLL fusions other than MLL-SEPT2, when compared with the normal control group (p = 0.023) We found a significant down-regulation of both SEPT2 and MLL in MLL-SEPT2 myeloid neoplasias. In addition, we also found that MLL is under-expressed in AML patients with MLL fusions other than MLL-SEPT2

  12. Dynamic increase and decrease of photonic crystal nanocavity Q factors for optical pulse control.

    Science.gov (United States)

    Upham, Jeremy; Tanaka, Yoshinori; Asano, Takashi; Noda, Susumu

    2008-12-22

    We introduce recent advances in dynamic control over the Q factor of a photonic crystal nanocavity system. By carefully timing a rapid increase of the Q factor from 3800 to 22,000, we succeed in capturing a 4ps signal pulse within the nanocavity with a photon lifetime of 18ps. By performing an additional transition of the Q factor within the photon lifetime, the held light is once again ejected from of the system on demand.

  13. Using a self-control training procedure to increase appropriate behavior.

    OpenAIRE

    Dixon, M R; Hayes, L J; Binder, L M; Manthey, S; Sigman, C; Zdanowski, D M

    1998-01-01

    The present study evaluated a technique for teaching self-control and increasing desirable behaviors among adults with developmental disabilities. Results showed that when participants were initially given the choice between an immediate smaller reinforcer and a larger delayed reinforcer, all participants repeatedly chose the smaller reinforcer. Concurrent fixed-duration/progressive-duration reinforcement schedules then were introduced in which initially both the smaller and larger reinforcer...

  14. Increase efficiency CNC lathe with the help of fuzzy logic controller (FLC

    Directory of Open Access Journals (Sweden)

    Mošorinski Predrag R.

    2016-01-01

    Full Text Available This paper discusses the process of increasing the effectiveness of CNC lathe for carrying out the appropriate experiments. Experiments are related to the plastics processing machine and programming fuzzy logic controller (FLC for the requirements of machining. Input parameters of the FLCare obtained as a result of previous experimental parameters set by experience and with a great subjective impact of technologists. Expected results of FLC's settings are based on the complete autonomy of the process and eliminating subjective errors.

  15. Activity of Bruton's tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: a mechanistic study using patient-derived blast cells.

    Science.gov (United States)

    Rushworth, Stuart A; Pillinger, Genevra; Abdul-Aziz, Amina; Piddock, Rachel; Shafat, Manar S; Murray, Megan Y; Zaitseva, Lyubov; Lawes, Matthew J; MacEwan, David J; Bowles, Kristian M

    2015-05-01

    Roughly 80% of patients with acute myeloid leukaemia have high activity of Bruton's tyrosine-kinase (BTK) in their blast cells compared with normal haemopoietic cells, rendering the cells sensitive to the oral BTK inhibitor ibrutinib in vitro. We aimed to develop the biological understanding of the BTK pathway in acute myeloid leukaemia to identify clinically relevant diagnostic information that might define a subset of patients that should respond to ibrutinib treatment. We obtained acute myeloid leukaemia blast cells from unselected patients attending our UK hospital between Feb 19, 2010, and Jan 20, 2014. We isolated primary acute myeloid leukaemia blast cells from heparinised blood and human peripheral blood mononuclear cells to establish the activity of BTK in response to CD117 activation. Furthermore, we investigated the effects of ibrutinib on CD117-induced BTK activation, downstream signalling, adhesion to primary bone-marrow mesenchymal stromal cells, and proliferation of primary acute myeloid leukaemia blast cells. We used the Mann-Whitney U test to compare results between groups. We obtained acute myeloid leukaemia blast cells from 29 patients. Ibrutinib significantly inhibited CD117-mediated proliferation of primary acute myeloid leukaemia blast cells (p=0·028). CD117 activation increased BTK activity by inducing phosphorylated BTK in patients with CD117-positive acute myeloid leukaemia. Furthermore, ibrutinib inhibited CD117-induced activity of BTK and downstream kinases at a concentration of 100 nM or more. CD117-mediated adhesion of CD117-expressing blast cells to bone-marrow stromal cells was significantly inhibited by Ibrutinib at 500 nM (p=0·028) INTERPRETATION: As first-in-man clinical trials of ibrutinib in patients with acute myeloid leukaemia commence, the data suggest not all patients will respond. Our findings show that BTK has specific pro-tumoural biological actions downstream of surface CD117 activation, which are inhibited by ibrutinib

  16. SAMHD1 restricts HIV-1 replication and regulates interferon production in mouse myeloid cells.

    Directory of Open Access Journals (Sweden)

    Ruonan Zhang

    Full Text Available SAMHD1 restricts the replication of HIV-1 and other retroviruses in human myeloid and resting CD4(+ T cells and that is counteracted in SIV and HIV-2 by the Vpx accessory protein. The protein is a phosphohydrolase that lowers the concentration of deoxynucleoside triphosphates (dNTP, blocking reverse transcription of the viral RNA genome. Polymorphisms in the gene encoding SAMHD1 are associated with Aicardi-Goutières Syndrome, a neurological disorder characterized by increased type-I interferon production. SAMHD1 is conserved in mammals but its role in restricting virus replication and controlling interferon production in non-primate species is not well understood. We show that SAMHD1 is catalytically active and expressed at high levels in mouse spleen, lymph nodes, thymus and lung. siRNA knock-down of SAMHD1 in bone marrow-derived macrophages increased their susceptibility to HIV-1 infection. shRNA knock-down of SAMHD1 in the murine monocytic cell-line RAW264.7 increased its susceptibility to HIV-1 and murine leukemia virus and increased the levels of the dNTP pool. In addition, SAMHD1 knock-down in RAW264.7 cells induced the production of type-I interferon and several interferon-stimulated genes, modeling the situation in Aicardi-Goutières Syndrome. Our findings suggest that the role of SAMHD1 in restricting viruses is conserved in the mouse. The RAW264.7 cell-line serves as a useful tool to study the antiviral and innate immune response functions of SAMHD1.

  17. Online distribution channel increases article usage on Mendeley: a randomized controlled trial.

    Science.gov (United States)

    Kudlow, Paul; Cockerill, Matthew; Toccalino, Danielle; Dziadyk, Devin Bissky; Rutledge, Alan; Shachak, Aviv; McIntyre, Roger S; Ravindran, Arun; Eysenbach, Gunther

    2017-01-01

    Prior research shows that article reader counts (i.e. saves) on the online reference manager, Mendeley, correlate to future citations. There are currently no evidenced-based distribution strategies that have been shown to increase article saves on Mendeley. We conducted a 4-week randomized controlled trial to examine how promotion of article links in a novel online cross-publisher distribution channel (TrendMD) affect article saves on Mendeley. Four hundred articles published in the Journal of Medical Internet Research were randomized to either the TrendMD arm ( n  = 200) or the control arm ( n  = 200) of the study. Our primary outcome compares the 4-week mean Mendeley saves of articles randomized to TrendMD versus control. Articles randomized to TrendMD showed a 77% increase in article saves on Mendeley relative to control. The difference in mean Mendeley saves for TrendMD articles versus control was 2.7, 95% CI (2.63, 2.77), and statistically significant ( p  < 0.01). There was a positive correlation between pageviews driven by TrendMD and article saves on Mendeley (Spearman's rho r  = 0.60). This is the first randomized controlled trial to show how an online cross-publisher distribution channel (TrendMD) enhances article saves on Mendeley. While replication and further study are needed, these data suggest that cross-publisher article recommendations via TrendMD may enhance citations of scholarly articles.

  18. Can a documentary increase help-seeking intentions in men? A randomised controlled trial.

    Science.gov (United States)

    King, Kylie Elizabeth; Schlichthorst, Marisa; Spittal, Matthew J; Phelps, Andrea; Pirkis, Jane

    2018-01-01

    We investigated whether a public health intervention-a three-part documentary called Man Up which explored the relationship between masculinity and mental health, well-being and suicidality-could increase men's intentions to seek help for personal and emotional problems. We recruited men aged 18 years or over who were not at risk of suicide to participate in a double-blind randomised controlled trial. Participants were randomly assigned (1:1) via computer randomisation to view Man Up (the intervention) or a control documentary. We hypothesised that 4 weeks after viewing Man Up participants would report higher levels of intention to seek help than those who viewed the control documentary. Our primary outcome was assessed using the General Help Seeking Questionnaire, and was analysed for all participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12616001169437, Universal Trial Number: U1111-1186-1459) and was funded by the Movember Foundation. Three hundred and fifty-four men were assessed for eligibility for the trial and randomised to view Man Up or the control documentary. Of these, 337 completed all stages (nine participants were lost to follow-up in the intervention group and eight in the control group). Linear regression analysis showed a significant increase in intentions to seek help in the intervention group, but not in the control group (coef.=2.06, 95% CI 0.48 to 3.63, P=0.01). Our trial demonstrates the potential for men's health outcomes to be positively impacted by novel, media-based public health interventions that focus on traditional masculinity. ACTRN12616001169437, Results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. The increased use of radiation requires enhanced activities regarding radiation safety control

    International Nuclear Information System (INIS)

    Lee, Yun Jong; Lee, Jin Woo; Jeong, Gyo Seong

    2015-01-01

    More recently, companies that have obtained permission to use radioactive materials or radiation device and registered radiation workers have increased by 10% and 4% respectively. The increased use of radiation could have an effect on radiation safety control. However, there is not nearly enough manpower and budget compared to the number of workers and facilities. This paper will suggest a counteroffer thought analyzing pending issues. The results of this paper indicate that there are 47 and 31.3 workers per radiation protection officer in educational and research institutes, respectively. There are 20.1 persons per RPO in hospitals, even though there are 2 RPOs appointed. Those with a special license as a radioisotope handler were ruled out as possible managers because medical doctors who have a special license for radioisotope handling normally have no experience with radiation safety. The number of staff members and budget have been insufficient for safety control at most educational and research institutes. It is necessary to build an optimized safety control system for effective Radiation Safety Control. This will reduce the risk factor of safety, and a few RPOs can be supplied for efficiency and convenience

  20. The increased use of radiation requires enhanced activities regarding radiation safety control

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yun Jong; Lee, Jin Woo; Jeong, Gyo Seong [Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of)

    2015-05-15

    More recently, companies that have obtained permission to use radioactive materials or radiation device and registered radiation workers have increased by 10% and 4% respectively. The increased use of radiation could have an effect on radiation safety control. However, there is not nearly enough manpower and budget compared to the number of workers and facilities. This paper will suggest a counteroffer thought analyzing pending issues. The results of this paper indicate that there are 47 and 31.3 workers per radiation protection officer in educational and research institutes, respectively. There are 20.1 persons per RPO in hospitals, even though there are 2 RPOs appointed. Those with a special license as a radioisotope handler were ruled out as possible managers because medical doctors who have a special license for radioisotope handling normally have no experience with radiation safety. The number of staff members and budget have been insufficient for safety control at most educational and research institutes. It is necessary to build an optimized safety control system for effective Radiation Safety Control. This will reduce the risk factor of safety, and a few RPOs can be supplied for efficiency and convenience.

  1. Effectiveness of a multi-level asthma intervention in increasing controller medication use: a randomized control trial.

    Science.gov (United States)

    Canino, Glorisa; Shrout, Patrick E; Vila, Doryliz; Ramírez, Rafael; Rand, Cynthia

    2016-01-01

    Poor self-management by families is an important factor in explaining high rates of asthma morbidity in Puerto Rico, and for this reason we previously tested a family intervention called CALMA that was found effective in improving most asthma outcomes, but not effective in increasing the use of controller medications. CALMA-plus was developed to address this issue by adding to CALMA, components of provider training and screening for asthma in clinics. Study participants were selected from claims Medicaid data in San Juan, Puerto Rico. After screening, 404 children in eight clinics were selected after forming pairs of clinics and randomizing the clinics) to CALMA-only or CALMA-plus. For all three primary outcomes at 12 months, the mean differences between treatment arms were small but in the predicted direction. However, after adjusting for clinic variation, the study failed to demonstrate that the CALMA-plus intervention was more efficacious than the CALMA-only intervention for increasing controller medication use, or decreasing asthma symptoms. Both groups had lower rates of asthma symptoms and service utilization, consistent with previous results of the CALMA-only intervention. Compliance of providers with the intervention and training, small number of clinics available and the multiple barriers experienced by providers for medicating may have been related to the lack of difference observed between the groups. Future interventions should respond to the limitations of the present study design and provide more resources to providers that will increase provider participation in training and implementation of the intervention.

  2. The use of controlled microbial cenoses in producers' link to increase steady functioning of artificial ecosystems

    Science.gov (United States)

    Somova, Lydia; Mikheeva, Galina; Somova, Lydia

    The life support systems (LSS) for long-term missions are to use cycling-recycling systems, including biological recycling. Simple ecosystems include 3 links: producers (plants), consumers (man, animals) and reducers (microorganisms). Microorganisms are substantial component of every link of LSS. Higher plants are the traditional regenerator of air and producer of food. They should be used in many successive generations of their reproduction in LSS. Controlled microbiocenoses can increase productivity of producer's link and protect plants from infections. The goal of this work was development of methodological bases of formation of stable, controlled microbiocenoses, intended for increase of productivity of plants and for obtaining ecologically pure production of plants. Main results of our investigations: 1. Experimental microbiocenoses, has been produced in view of the developed methodology on the basis of natural association of microorganisms by long cultivation on specially developed medium. Dominating groups are bacteria of genera: Lactobacillus, Streptococcus, Leuconostoc, Bifidobacterium, Rhodopseudomonas and yeast of genera: Kluyveromyces, Saccharomyces, Torulopsis. 2. Optimal parameters of microbiocenosis cultivation (t, pH, light exposure, biogenic elements concentrations) were experimentally established. Conditions of cultivation on which domination of different groups of microbiocenosis have been found. 3. It was shown, that processing of seeds of wheat, oats, bulbs and plants Allium cepa L. (an onions) with microbial association raised energy of germination of seeds and bulbs and promoted the increase (on 20-30 %) of growth green biomass and root system of plants in comparison with the control. This work is supported by grant, Yenissey , 07-04-96806

  3. Publications as an indicator of increased tobacco control research productivity (quantity and quality) in New Zealand.

    Science.gov (United States)

    Kira, Anette; Glover, Marewa; Bullen, Chris; Viehbeck, Sarah

    2011-06-01

    Tobacco control (TC) research capacity and productivity are critical for developing evidence-informed interventions that will reduce the harmful effects of smoking. The aim of this paper was to investigate New Zealand's (NZ) TC research capacity along with the quantity and quality of publications, following two government initiatives aimed, in part, at improving the quantity and quality of NZ TC research. Scopus was searched for articles with at least one NZ author and where the topic was of primary relevance to TC. Publications were organized into two time periods, following the government initiatives, 1993-2003 and 2004-2009. We analyzed the number of publications, publication journals, type of publications, impact (using the impact factor), and authorship. There has been an increase in number and impact of publications and number of authors. The number of publications has increased from an average of 14 (1994-2003) to 38 per year (2004-2009). The number of journals published increased from 64 to 86. The impact during 2004-2009 was almost threefold than in 1993-2003. The number of authors increased from 212 to 345, and the number of authors who had at least one first-authored publication increased from 80 to 124. These results show an encouraging trend in NZ TC research, with an increase in research productivity, quality, and in research capacity. It is possible that government-initiated and -funded infrastructural support contributed to increasing needed TC research, which supports the worth of such initiatives.

  4. Increasing power generation in horizontal axis wind turbines using optimized flow control

    Science.gov (United States)

    Cooney, John A., Jr.

    In order to effectively realize future goals for wind energy, the efficiency of wind turbines must increase beyond existing technology. One direct method for achieving increased efficiency is by improving the individual power generation characteristics of horizontal axis wind turbines. The potential for additional improvement by traditional approaches is diminishing rapidly however. As a result, a research program was undertaken to assess the potential of using distributed flow control to increase power generation. The overall objective was the development of validated aerodynamic simulations and flow control approaches to improve wind turbine power generation characteristics. BEM analysis was conducted for a general set of wind turbine models encompassing last, current, and next generation designs. This analysis indicated that rotor lift control applied in Region II of the turbine power curve would produce a notable increase in annual power generated. This was achieved by optimizing induction factors along the rotor blade for maximum power generation. In order to demonstrate this approach and other advanced concepts, the University of Notre Dame established the Laboratory for Enhanced Wind Energy Design (eWiND). This initiative includes a fully instrumented meteorological tower and two pitch-controlled wind turbines. The wind turbines are representative in their design and operation to larger multi-megawatt turbines, but of a scale that allows rotors to be easily instrumented and replaced to explore new design concepts. Baseline data detailing typical site conditions and turbine operation is presented. To realize optimized performance, lift control systems were designed and evaluated in CFD simulations coupled with shape optimization tools. These were integrated into a systematic design methodology involving BEM simulations, CFD simulations and shape optimization, and selected experimental validation. To refine and illustrate the proposed design methodology, a

  5. Increasing girls’ physical activity during an organised youth sport basketball program: a randomised controlled trial protocol

    Science.gov (United States)

    2014-01-01

    Background Participation in organised youth sports (OYS) has been recommended as an opportunity to increase young peoples’ moderate-to-vigorous physical activity (MVPA) levels. Participants, however, spend a considerable proportion of time during OYS inactive. The purpose of this study, therefore, was to investigate whether coaches who attended coach education sessions (where education on increasing MVPA and decreasing inactivity during training was delivered) can increase players’ MVPA during training sessions over a 5-day basketball program compared to coaches who did not receive coach education sessions. Methods/design A convenience sample of 80 female players and 8 coaches were recruited into the UWS School Holiday Basketball Program in Greater Western Sydney, Australia. A two-arm, parallel-group randomised controlled trial was employed to investigate whether coaches who attended 2 coach education sessions (compared with a no-treatment control) can increase their players’ MVPA during training sessions over a 5-day basketball program. Objectively measured physical activity, directly observed lesson context and leader behaviour, player motivation, players’ perceived autonomy support, and coaching information (regarding training session planning, estimations on player physical activity and lesson context during training, perceived ability to modify training sessions, perceived importance of physical activity during training, intention to increase physical activity/reduce inactivity, and likelihood of increasing physical activity/reducing inactivity) were assessed at baseline (day 1) and at follow-up (day 5). Linear mixed models will be used to analyse between arm differences in changes from baseline to follow-up on all outcomes. Discussion The current trial protocol describes, to our knowledge, the first trial conducted in an OYS context to investigate the efficacy of an intervention, relative to a control, in increasing MVPA. This study’s findings will

  6. Reactive oxygen species activate differentiation gene transcription of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway.

    Science.gov (United States)

    Lam, Chung Fan; Yeung, Hoi Ting; Lam, Yuk Man; Ng, Ray Kit

    2018-05-01

    Reactive oxygen species (ROS) and altered cellular redox status are associated with many malignancies. Acute myeloid leukemia (AML) cells are maintained at immature state by differentiation blockade, which involves deregulation of transcription factors in myeloid differentiation. AML cells can be induced to differentiate by phorbol-12-myristate-13-acetate (PMA), which possesses pro-oxidative activity. However, the signaling events mediated by ROS in the activation of transcriptional program during AML differentiation has not been fully elucidated. Here, we investigated AML cell differentiation by treatment with PMA and ROS scavenger N-acetyl-l-cysteine (NAC). We observed elevation of intracellular ROS level in the PMA-treated AML cells, which correlated with differentiated cell morphology and increased CD11b + mature cell population. The effect of PMA can be abolished by NAC co-treatment, supporting the involvement of ROS in the process. Moreover, we demonstrated that short ROS elevation mediated cell cycle arrest, but failed to activate myeloid gene transcription; whereas prolonged ROS elevation activated JNK/c-JUN signaling pathway. Inhibition of JNK suppressed the expression of key myeloid transcriptional regulators c-JUN, SPI-1 and MAFB, and prevented AML cells from undergoing terminal differentiation. These findings provide new insights into the crucial role of JNK/c-Jun signaling pathway in the activation of transcriptional program during ROS-mediated AML differentiation. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Increasing Mn substitution in magnetic semiconductors through controlled ambient annealing processes

    Energy Technology Data Exchange (ETDEWEB)

    Hollingsworth, J. [Materials Science Program, Department of Mechanical and Aerospace Engineering, UC San Diego, La Jolla, CA 92093-0411 (United States); Bandaru, P.R. [Materials Science Program, Department of Mechanical and Aerospace Engineering, UC San Diego, La Jolla, CA 92093-0411 (United States)], E-mail: pbandaru@ucsd.edu

    2008-06-25

    We report on a controlled ambient annealing technique aimed at increasing the amount of Mn incorporation in III-V semiconductors. The aim is to reduce the number of hole carrier and magnetic element compensating entities, such as Mn interstitials and anti-site defects, to increase the magnetic Curie temperature. The idea is (a) to increase the number of Group III vacancies through annealing in Group V vapor rich conditions and (b) judicious use of crystal field theory to reduce/stabilize Mn interstitials. Our experimental results constitute the highest reportedT{sub c} ({approx}130 K) in Mn doped InSb and Mn doped InP. The possibility of ferrimagnetism in Mn and Cr incorporated GaAs, was noted.

  8. Control of a hybrid HVDC link to increase inter-regional power transfer

    DEFF Research Database (Denmark)

    Kotb, Omar; Ghandhari, Mehrdad; Eriksson, Robert

    2016-01-01

    This paper examines the application of a hybrid HVDC link in a two area power system with the purpose of increasing the inter-regional power transfer. A hybrid HVDC system combines both LCCs and VSCs, and hence it is capable of combining the benefits of both converter technologies, such as reduced...... cost and power losses due to the LCCs, and ability to connect to weak AC grids due to the VSCs. The mathematical model of the power system including the HVDC link is presented. The increase in inter-area power transfer is demonstrated and compared to the case when the hybrid HVDC link is not used....... Furthermore, the transient stability of the AC/DC power system was enhanced using auxiliary controllers for Power Oscillation Damping (POD). The results show the ability of the hybrid HVDC link to increase the unidirectional inter-area power transfer, while enhancing the transient stability of the power...

  9. Myeloid translocation genes differentially regulate colorectal cancer programs

    Science.gov (United States)

    Parang, Bobak; Bradley, Amber M.; Mittal, Mukul K.; Short, Sarah P.; Thompson, Joshua J.; Barrett, Caitlyn W.; Naik, Rishi D.; Bilotta, Anthony J.; Washington, Mary K.; Revetta, Frank L.; Smith, Jesse J.; Chen, Xi; Wilson, Keith T.; Hiebert, Scott W.; Williams, Christopher S.

    2016-01-01

    Myeloid translocation genes (MTGs), originally identified as chromosomal translocations in acute myelogenous leukemia, are transcriptional corepressors that regulate hematopoietic stem cell programs. Analysis of The Cancer Genome Atlas (TCGA) database revealed that MTGs were mutated in epithelial malignancy and suggested that loss of function might promote tumorigenesis. Genetic deletion of MTGR1 and MTG16 in the mouse has revealed unexpected and unique roles within the intestinal epithelium. Mtgr1−/− mice have progressive depletion of all intestinal secretory cells, and Mtg16−/− mice have a decrease in goblet cells. Furthermore, both Mtgr1−/− and Mtg16−/− mice have increased intestinal epithelial cell proliferation. We thus hypothesized that loss of MTGR1 or MTG16 would modify Apc1638/+-dependent intestinal tumorigenesis. Mtgr1−/− mice, but not Mtg16−/− mice, had a 10-fold increase in tumor multiplicity. This was associated with more advanced dysplasia, including progression to invasive adenocarcinoma, and augmented intratumoral proliferation. Analysis of ChIP-seq datasets for MTGR1 and MTG16 targets indicated that MTGR1 can regulate Wnt and Notch signaling. In support of this, immunohistochemistry and gene expression analysis revealed that both Wnt and Notch signaling pathways were hyperactive in Mtgr1−/− tumors. Furthermore, in human colorectal cancer (CRC) samples MTGR1 was downregulated at both the transcript and protein level. Overall our data indicates that MTGR1 has a context dependent effect on intestinal tumorigenesis. PMID:27270437

  10. Increased brain connectivity and activation after cognitive rehabilitation in Parkinson's disease: a randomized controlled trial.

    Science.gov (United States)

    Díez-Cirarda, María; Ojeda, Natalia; Peña, Javier; Cabrera-Zubizarreta, Alberto; Lucas-Jiménez, Olaia; Gómez-Esteban, Juan Carlos; Gómez-Beldarrain, Maria Ángeles; Ibarretxe-Bilbao, Naroa

    2017-12-01

    Cognitive rehabilitation programs have demonstrated efficacy in improving cognitive functions in Parkinson's disease (PD), but little is known about cerebral changes associated with an integrative cognitive rehabilitation in PD. To assess structural and functional cerebral changes in PD patients, after attending a three-month integrative cognitive rehabilitation program (REHACOP). Forty-four PD patients were randomly divided into REHACOP group (cognitive rehabilitation) and a control group (occupational therapy). T1-weighted, diffusion weighted and functional magnetic resonance images (fMRI) during resting-state and during a memory paradigm (with learning and recognition tasks) were acquired at pre-treatment and post-treatment. Cerebral changes were assessed with repeated measures ANOVA 2 × 2 for group x time interaction. During resting-state fMRI, the REHACOP group showed significantly increased brain connectivity between the left inferior temporal lobe and the bilateral dorsolateral prefrontal cortex compared to the control group. Moreover, during the recognition fMRI task, the REHACOP group showed significantly increased brain activation in the left middle temporal area compared to the control group. During the learning fMRI task, the REHACOP group showed increased brain activation in the left inferior frontal lobe at post-treatment compared to pre-treatment. No significant structural changes were found between pre- and post-treatment. Finally, the REHACOP group showed significant and positive correlations between the brain connectivity and activation and the cognitive performance at post-treatment. This randomized controlled trial suggests that an integrative cognitive rehabilitation program can produce significant functional cerebral changes in PD patients and adds evidence to the efficacy of cognitive rehabilitation programs in the therapeutic approach for PD.

  11. Increasing organ donation via anticipated regret (INORDAR: protocol for a randomised controlled trial

    Directory of Open Access Journals (Sweden)

    O'Carroll Ronan E

    2012-03-01

    Full Text Available Abstract Background Throughout the world there is an insufficient supply of donor organs to meet the demand for organ transplantations. This paper presents a protocol for a randomised controlled trial, testing whether a simple, theory-based anticipated regret manipulation leads to a significant increase in posthumous organ donor registrations. Methods We will use a between-groups, prospective randomised controlled design. A random sample of 14,520 members of the adult Scottish general public will be contacted via post. These participants will be randomly allocated into 1 of the 4 conditions. The no questionnaire control (NQC group will simply receive a letter and donor registration form. The questionnaire control (QC arm will receive a questionnaire measuring their emotions and non-cognitive affective attitudes towards organ donation. The theory of planned behavior (TPB group will complete the emotions and affective attitudes questionnaire plus additional items assessing their cognitive attitudes towards organ donation, perceived control over registration and how they think significant others view this action. Finally, the anticipated regret (AR group will complete the same indices as the TPB group, plus two additional anticipated regret items. These items will assess the extent to which the participant anticipates regret for not registering as an organ donor in the near future. The outcome variable will be NHS Blood and Transplant verified registrations as an organ donor within 6 months of receiving our postal intervention. Discussion This study will assess whether simply asking people to reflect on the extent to which they may anticipate regret for not registering as an organ donor increases organ donor registration 6 months later. If successful, this simple and easy to administer theory-based intervention has the potential to save lives and money for the NHS by reducing the number of people receiving treatments such as dialysis. This

  12. Increase in oxidative stress levels following welding fume inhalation: a controlled human exposure study.

    Science.gov (United States)

    Graczyk, Halshka; Lewinski, Nastassja; Zhao, Jiayuan; Sauvain, Jean-Jacques; Suarez, Guillaume; Wild, Pascal; Danuser, Brigitta; Riediker, Michael

    2016-06-10

    Tungsten inert gas (TIG) welding represents one of the most widely used metal joining processes in industry. It has been shown to generate a large majority of particles at the nanoscale and to have low mass emission rates when compared to other types of welding. Despite evidence that TIG fume particles may produce reactive oxygen species (ROS), limited data is available for the time course changes of particle-associated oxidative stress in exposed TIG welders. Twenty non-smoking male welding apprentices were exposed to TIG welding fumes for 60 min under controlled, well-ventilated settings. Exhaled breathe condensate (EBC), blood and urine were collected before exposure, immediately after exposure, 1 h and 3 h post exposure. Volunteers participated in a control day to account for oxidative stress fluctuations due to circadian rhythm. Biological liquids were assessed for total reducing capacity, hydrogen peroxide (H2O2), malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations at each time point. A linear mixed model was used to assess within day and between day differences. Significant increases in the measured biomarkers were found at 3 h post exposure. At 3 h post exposure, we found a 24 % increase in plasma-H2O2 concentrations ([95%CI: 4 % to 46 %], p = 0.01); a 91 % increase in urinary-H2O2 ([2 % to 258 %], p = 0.04); a 14 % increase in plasma-8-OHdG ([0 % to 31 %], p = 0.049); and a 45 % increase in urinary-8-OHdG ([3 % to 105 %], p = 0.03). Doubling particle number concentration (PNC) exposure was associated with a 22 % increase of plasma-8-OHdG at 3 h post exposure (p = 0.01). A 60-min exposure to TIG welding fume in a controlled, well-ventilated setting induced acute oxidative stress at 3 h post exposure in healthy, non-smoking apprentice welders not chronically exposed to welding fumes. As mass concentration of TIG welding fume particles is very low when compared to other types of welding, it is

  13. An acute exercise session increases self-efficacy in sedentary endometrial cancer survivors and controls.

    Science.gov (United States)

    Hughes, Daniel; Baum, George; Jovanovic, Jennifer; Carmack, Cindy; Greisinger, Anthony; Basen-Engquist, Karen

    2010-11-01

    Self-efficacy can be affected by mastery experiences and somatic sensations. A novel exercise experience and associated sensations may impact self-efficacy and subsequent behaviors. We investigated the effect of a single exercise session on self-efficacy for sedentary endometrial cancer survivors compared with sedentary women of a similar age, but with no cancer history. Twenty survivors and 19 controls completed an exercise session performed as a submaximal cycle ergometry test. Sensations and efficacy were measured before and after exercise. Repeated measures analysis of variance (ANOVA) was performed. Regression models were used to determine predictors of self-efficacy and subsequent exercise. Self-efficacy increased for both survivors and controls, but survivors had a higher rate of increase, and the change predicted subsequent exercise. The association between exercise-related somatic sensations and self-efficacy differed between the 2 groups. A novel exercise experience had a larger effect on self-efficacy and subsequent exercise activity for endometrial cancer survivors than controls. Somatic sensations experienced during exercise may differ for survivors, which may be related to the experience of having cancer. Understanding factors affecting confidence in novel exercise experiences for populations with specific cancer histories is of the utmost importance in the adoption of exercise behaviors.

  14. Chocolate bar as an incentive did not increase response rate among physiotherapists: a randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Dahm Kristin

    2008-06-01

    Full Text Available Abstract Background The aim of this study was to assess the effect of a small incentive, a bar of dark chocolate, on response rate in a study of physiotherapy performance in patients with knee osteoarthritis. Findings Norwegian physiotherapists from private practice were randomised in blocks to an intervention group (n = 1027 receiving a bar of dark chocolate together with a data-collection form, and a control group (n = 1027 that received the data-collection form only. The physiotherapists were asked to prospectively complete the data-collection form by reporting treatments provided to one patient with knee osteoarthritis through 12 treatment sessions. The outcome measure was response rate of completed forms. Out of the 510 physiotherapists that responded, 280 had completed the data-collection form by the end of the study period. There was no difference between the chocolate and no-chocolate group in response rate of those who sent in completed forms. In the chocolate group, 142 (13.8% returned completed forms compared to 138 (13.4% in the control group, ARR = 0.4 (95% CI: -3.44 to 2.6. Conclusion A bar of dark chocolate did not increase response rate in a prospective study of physiotherapy performance. Stronger incentives than chocolate seem to be necessary to increase the response rate among professionals who are asked to report about their practice. Trial Registration Current Controlled Trials register: ISRCTN02397855

  15. A multistage controlled intervention to increase stair climbing at work: effectiveness and process evaluation.

    Science.gov (United States)

    Bellicha, Alice; Kieusseian, Aurélie; Fontvieille, Anne-Marie; Tataranni, Antonio; Copin, Nane; Charreire, Hélène; Oppert, Jean-Michel

    2016-04-11

    Stair climbing helps to accumulate short bouts of physical activity throughout the day as a strategy for attaining recommended physical activity levels. There exists a need for effective long-term stair-climbing interventions that can be transferred to various worksite settings. The aims of this study were: 1) to evaluate short- and long-term effectiveness of a worksite stair-climbing intervention using an objective measurement of stair climbing and a controlled design; and 2) to perform a process evaluation of the intervention. We performed a controlled before-and-after study. The study was conducted in two corporate buildings of the same company located in Paris (France), between September, 2013 and September, 2014. The status of either "intervention site" or "control site" was assigned by the investigators. Participants were on-site employees (intervention site: n = 783; control site: n = 545 at baseline). Two one-month intervention phases using signs (intervention phase 1) and enhancement of stairwell aesthetics (intervention phase 2) were performed. The main outcome was the change in stair climbing, measured with automatic counters and expressed in absolute counts/day/100 employees and percent change compared to baseline. Qualitative outcomes were used to describe the intervention process. Stair climbing significantly increased at the intervention site (+18.7%) but decreased at the control site (-13.3%) during the second intervention phase (difference between sites: +4.6 counts/day/100 employees, p levels at the intervention site, but a significant difference between sites was found (intervention site vs. control site: +2.9 counts/day/100 employees, p level after the end of the study. This study shows a successful stair-climbing intervention at the worksite. The main barriers to adoption and implementation were related to location and visibility of posters. Process evaluation was useful in identifying these barriers throughout the study, and in

  16. Increased frontal electroencephalogram theta amplitude in patients with anorexia nervosa compared to healthy controls

    Directory of Open Access Journals (Sweden)

    Hestad KA

    2016-09-01

    Full Text Available Knut A Hestad,1–3 Siri Weider,3,4 Kristian Bernhard Nilsen,5–7 Marit Sæbø Indredavik,8,9 Trond Sand7,10 1Department of Research, Innlandet Hospital Trust, Brumunddal, Norway; 2Department of Public Health, Hedmark University of Applied Sciences, Elverum, Norway; 3Department of Psychology, Faculty of Social Sciences and Technology Management, Norwegian University of Science and Technology (NTNU, Trondheim, Norway; 4Department of Psychiatry, Specialised Unit for Eating Disorder Patients, Levanger Hospital, Health Trust Nord-Trøndelag, Levanger, Norway; 5Department of Neuroscience, Norwegian University of Science and Technology (NTNU, Trondheim, Norway; 6Department of Work Psychology and Physiology, National Institute of Occupational Health, Oslo, Norway; 7Department of Neurology, Section for Clinical Neurophysiology, Oslo University Hospital, Ullevål, Oslo, Norway; 8Regional Centre for Child and Youth Mental Health and Child Welfare, Faculty of Medicine, Norwegian University of Science and Technology (NTNU, Trondheim, Norway; 9Department of Child and Adolescent Psychiatry, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 10Department of Neurology and Clinical Neurophysiology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway Objective: To conduct a blind study of quantitative electroencephalogram-band amplitudes in patients with anorexia nervosa (AN and healthy controls.Methods: Twenty-one patients with AN and 24 controls were examined with eyes-closed 16-channel electroencephalogram. Main variables were absolute alpha, theta, and delta amplitudes in frontal, temporal, and posterior regions.Results: There were no significant differences between the AN patients and controls regarding absolute regional band amplitudes in µV. Borderline significance was found for anterior theta (P=0.051. Significantly increased left and right frontal electrode theta amplitude was found in AN patients (F3, P=0.014; F4, P

  17. Chronic autoimmune disorders are increased in coeliac disease: A case-control study.

    Science.gov (United States)

    Bibbò, Stefano; Pes, Giovanni Mario; Usai-Satta, Paolo; Salis, Roberta; Soro, Sara; Quarta Colosso, Bianca Maria; Dore, Maria Pina

    2017-11-01

    Coeliac disease (CD) is an autoimmune disorder of the small bowel associated with increased risk of additional autoimmune diseases (ADs).To investigate the prevalence of ADs in a population of adult coeliac patients.This was a retrospective case-control study. Data from coeliac patients and controls referred to a tertiary center between 2013 and 2016 were collected. The frequency of ADs and the unadjusted and adjusted odds ratios (ORs) for age, gender, disease duration, and body mass index with their 95% confidence intervals (CIs) were evaluated.Two hundred fifty-five patients with CD (median age 37.1 years; 206 women) were matched with 250 controls. ADs were more frequent (35.3%) in coeliac patients than in controls (15.2%). Adjusted ORs for the presence of only 1, at least 1, and more than 1 AD were 3.13 (95% CI 1.81-5.42, P disease. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

  18. Method and apparatus for a nuclear reactor for increasing reliability to scram control elements

    International Nuclear Information System (INIS)

    Bevilacqua, F.

    1976-01-01

    A description is given of a method and apparatus for increasing the reliability of linear drive devices of a nuclear reactor to scram the control elements held in a raised position thereby. Each of the plurality of linear drive devices includes a first type of holding means associated with the drive means of the linear drive device and a second type of holding means distinct and operatively dissimilar from the first type. The system of linear drive devices having both types of holding means are operated in such a manner that the control elements of a portion of the linear drive devices are only held in a raised position by the first holding means and the control elements of the remaining portion of linear drive devices are held in a raised position by only the second type of holding means. Since the two types of holding means are distinct from one another and are operatively dissimilar, the probability of failure of both systems to scram as a result of common mode failure will be minimized. Means may be provided to positively detect disengagement of the first type of holding means and engagement of the second type of holding means for those linear drive devices being operative to hold the control elements in a raised position with the second type of holding means

  19. Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control.

    Science.gov (United States)

    Cantu, David; Walker, Kendall; Andresen, Lauren; Taylor-Weiner, Amaro; Hampton, David; Tesco, Giuseppina; Dulla, Chris G

    2015-08-01

    Traumatic brain injury (TBI) is a major risk factor for developing pharmaco-resistant epilepsy. Although disruptions in brain circuitry are associated with TBI, the precise mechanisms by which brain injury leads to epileptiform network activity is unknown. Using controlled cortical impact (CCI) as a model of TBI, we examined how cortical excitability and glutamatergic signaling was altered following injury. We optically mapped cortical glutamate signaling using FRET-based glutamate biosensors, while simultaneously recording cortical field potentials in acute brain slices 2-4 weeks following CCI. Cortical electrical stimulation evoked polyphasic, epileptiform field potentials and disrupted the input-output relationship in deep layers of CCI-injured cortex. High-speed glutamate biosensor imaging showed that glutamate signaling was significantly increased in the injured cortex. Elevated glutamate responses correlated with epileptiform activity, were highest directly adjacent to the injury, and spread via deep cortical layers. Immunoreactivity for markers of GABAergic interneurons were significantly decreased throughout CCI cortex. Lastly, spontaneous inhibitory postsynaptic current frequency decreased and spontaneous excitatory postsynaptic current increased after CCI injury. Our results suggest that specific cortical neuronal microcircuits may initiate and facilitate the spread of epileptiform activity following TBI. Increased glutamatergic signaling due to loss of GABAergic control may provide a mechanism by which TBI can give rise to post-traumatic epilepsy. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Increased Prevalence of Colorectal Polyp in Acromegaly Patients: A Case-Control Study

    Directory of Open Access Journals (Sweden)

    Ali Riza Koksal

    2014-01-01

    Full Text Available An increase in the prevalence of colorectal polyps and cancer is reported in patients with acromegaly. This trial is designed to determine whether there is an increase in the prevalence of colorectal polyps/cancer in Turkish acromegaly patients. Sixty-six patients, who were under follow-up with the diagnosis of acromegaly and underwent total colonoscopic examination, were enrolled in the study. Sixty-five age- and gender-matched patients with nonspecific complaints were selected as control. The mean age of acromegalic patients was 51.5±12.8 years of whom 27 (40.9% were females. In 20 (30.3% of the patients with acromegaly a total of 65 colorectal polyps were detected. Forty-seven (72.3% of the polyps were detected at the rectosigmoid region. In 8 (12.3% of the 65 control patients a total of 17 polyps were found. There was a statistically significant difference between the groups (P=0.018. At the logistic regression analysis we found that the risk for colon polyps increased 3.2-fold in the presence of acromegaly, irrespective of age and gender (OR: 3.191, 95% CI: 1.25–8.13. In conclusion, patients who were followed up with the diagnosis of acromegaly should be taken to the colonoscopic surveillance program and all polyps detected should be excised in order to protect them from colorectal cancer.

  1. Re-Engineering the ISS Payload Operations Control Center During Increased Utilization and Critical Onboard Events

    Science.gov (United States)

    Dudley, Stephanie R. B.; Marsh, Angela L.

    2014-01-01

    With an increase in utilization and hours of payload operations being executed onboard the International Space Station (ISS), upgrading the NASA Marshall Space Flight Center (MSFC) Huntsville Operations Support Center (HOSC) ISS Payload Control Area (PCA) was essential to gaining efficiencies and assurance of current and future payload health and science return. PCA houses the Payload Operations Integration Center (POIC) responsible for the execution of all NASA payloads onboard the ISS. POIC Flight Controllers are responsible for the operation of voice, stowage, command, telemetry, video, power, thermal, and environmental control in support of ISS science experiments. The methodologies and execution of the PCA refurbishment were planned and performed within a four-month period in order to assure uninterrupted operation of ISS payloads and minimal impacts to payload operations teams. To vacate the PCA, three additional HOSC control rooms were reconfigured to handle ISS real-time operations, Backup Control Center (BCC) to Mission Control in Houston, simulations, and testing functions. This involved coordination and cooperation from teams of ISS operations controllers, multiple engineering and design disciplines, management, and construction companies performing an array of activities simultaneously and in sync delivering a final product with no issues that impacted the schedule. For each console operator discipline, studies of Information Technology (IT) tools and equipment layouts, ergonomics, and lines of sight were performed. Infusing some of the latest IT into the project was an essential goal in ensuring future growth and success of the ISS payload science returns. Engineering evaluations led to a state of the art Video Wall implementation and more efficient ethernet cabling distribution providing the latest products and the best solution for the POIC. These engineering innovations led to cost savings for the project. Constraints involved in the management of

  2. Avocado Consumption Increases Macular Pigment Density in Older Adults: A Randomized, Controlled Trial

    Directory of Open Access Journals (Sweden)

    Tammy M. Scott

    2017-08-01

    Full Text Available Lutein is selectively incorporated into the macula and brain. Lutein levels in the macula (macular pigment; MP and the brain are related to better cognition. MP density (MPD is a biomarker of brain lutein. Avocados are a bioavailable source of lutein. This study tests the effects of the intake of avocado on cognition. This was a six-month, randomized, controlled trial. Healthy subjects consumed one avocado (n = 20, 0.5 mg/day lutein, AV vs. one potato or one cup of chickpeas (n = 20, 0 mg/day lutein, C. Serum lutein, MPD, and cognition were assessed at zero, three, and six months. Primary analyses were conducted according to intent-to-treat principles, with repeated-measures analysis. At six months, AV increased serum lutein levels by 25% from baseline (p = 0.001. C increased by 15% (p = 0.030. At six months, there was an increase in MPD from baseline in AV (p = 0.001 and no increase in C. For both groups, there was an improvement in memory and spatial working memory (p = 0.001; p = 0.032, respectively. For AV only there was improved sustained attention (p = 0.033, and the MPD increase was related to improved working memory and efficiency in approaching a problem (p = 0.036. Dietary recommendations including avocados may be an effective strategy for cognitive health.

  3. Avocado Consumption Increases Macular Pigment Density in Older Adults: A Randomized, Controlled Trial.

    Science.gov (United States)

    Scott, Tammy M; Rasmussen, Helen M; Chen, Oliver; Johnson, Elizabeth J

    2017-08-23

    Lutein is selectively incorporated into the macula and brain. Lutein levels in the macula (macular pigment; MP) and the brain are related to better cognition. MP density (MPD) is a biomarker of brain lutein. Avocados are a bioavailable source of lutein. This study tests the effects of the intake of avocado on cognition. This was a six-month, randomized, controlled trial. Healthy subjects consumed one avocado ( n = 20, 0.5 mg/day lutein, AV) vs. one potato or one cup of chickpeas ( n = 20, 0 mg/day lutein, C). Serum lutein, MPD, and cognition were assessed at zero, three, and six months. Primary analyses were conducted according to intent-to-treat principles, with repeated-measures analysis. At six months, AV increased serum lutein levels by 25% from baseline ( p = 0.001). C increased by 15% ( p = 0.030). At six months, there was an increase in MPD from baseline in AV ( p = 0.001) and no increase in C. For both groups, there was an improvement in memory and spatial working memory ( p = 0.001; p = 0.032, respectively). For AV only there was improved sustained attention ( p = 0.033), and the MPD increase was related to improved working memory and efficiency in approaching a problem ( p = 0.036). Dietary recommendations including avocados may be an effective strategy for cognitive health.

  4. Serum concentrations of nitrite and malondialdehyde as markers of oxidative stress in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

    Directory of Open Access Journals (Sweden)

    Maria Juracy Petrola

    2012-01-01

    Full Text Available BACKGROUND: Chronic myeloid leukemia is a neoplasm characterized by clonal expansion of hematopoietic progenitor cells resulting from the (9:22(q34,11 translocation. The tyrosine kinase abl fusion protein,the initial leukemogenic event in chronic myeloid leukemia, is constitutively activated thus inducing the production of reactive oxygen species. Of particular relevance is the fact that an increase in reactive oxygen species can facilitate genomic instability and may contribute to disease progression. OBJETIVE: To evaluate oxidative stress by determining the levels of malondialdehyde and nitrite in chronic myeloid leukemia patients under treatment with 1st and 2nd generation tyrosine kinase inhibitors monitored at a referral hospital in Fortaleza, Ceará. METHODS: A cross-sectional study was performed of 64 male and female adults. Patients were stratified according to treatment. The levels of malondialdehyde and nitrite were determined by spectrophotometry. Statistical differences between groups were observed using the Student t-test and Fisher's exact test. The results are expressed as mean ± standard error of mean. The significance level was set for a p-value < 0.05 in all analyses. RESULTS: The results show significantly higher mean concentrations of nitrite and malondialdehyde in chronic myeloid leukemia patients using second-generation tyrosine kinase inhibitors compared to patients on imatinib. Conclusion: It follows that chronic myeloid leukemia patients present higher oxidative activity and that the increases in oxidative damage markers can indicate resistance to 1st generation tyrosine kinase inhibitors.

  5. Retroviruses As Myeloid Cell Riders: What Natural Human Siglec-1 “Knockouts” Tell Us About Pathogenesis

    Directory of Open Access Journals (Sweden)

    Javier Martinez-Picado

    2017-11-01

    Full Text Available Myeloid cells initiate immune responses and are crucial to control infections. In the case of retroviruses, however, myeloid cells also promote pathogenesis by enabling viral dissemination; a process extensively studied in vitro using human immunodeficiency virus type 1 (HIV-1. This viral hijacking mechanism does not rely on productive myeloid cell infection but requires HIV-1 capture via Siglec-1/CD169, a receptor expressed on myeloid cells that facilitates the infection of bystander target cells. Murine retroviruses are also recognized by Siglec-1, and this interaction is required for robust retroviral infection in vivo. Yet, the relative contribution of Siglec-1-mediated viral dissemination to HIV-1 disease progression remains unclear. The identification of human null individuals lacking working copies of a particular gene enables studying how this loss affects disease progression. Moreover, it can reveal novel antiviral targets whose blockade might be therapeutically effective and safe, since finding null individuals in natura uncovers dispensable functions. We previously described a loss-of-function variant in SIGLEC-1. Analysis of a large cohort of HIV-1-infected individuals identified homozygous and heterozygous subjects, whose cells were functionally null or partially defective for Siglec-1 activity in HIV-1 capture and transmission ex vivo. Nonetheless, analysis of the effect of Siglec-1 truncation on progression to AIDS was not conclusive due to the limited cohort size, the lack of complete clinical records, and the restriction to study only off-therapy periods. Here, we review how the study of loss-of-function variants might serve to illuminate the role of myeloid cells in viral pathogenesis in vivo and the challenges ahead.

  6. Increasing Fuel Efficiency of Direct Methanol Fuel Cell Systems with Feedforward Control of the Operating Concentration

    Directory of Open Access Journals (Sweden)

    Youngseung Na

    2015-09-01

    Full Text Available Most of the R&D on fuel cells for portable applications concentrates on increasing efficiencies and energy densities to compete with other energy storage devices, especially batteries. To improve the efficiency of direct methanol fuel cell (DMFC systems, several modifications to system layouts and operating strategies are considered in this paper, rather than modifications to the fuel cell itself. Two modified DMFC systems are presented, one with an additional inline mixer and a further modification of it with a separate tank to recover condensed water. The set point for methanol concentration control in the solution is determined by fuel efficiency and varies with the current and other process variables. Feedforward concentration control enables variable concentration for dynamic loads. Simulation results were validated experimentally with fuel cell systems.

  7. Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia

    KAUST Repository

    Madhoun, Nour Y.

    2017-01-01

    Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation

  8. In vivo RNAi screening for the identification of oncogenes and tumor suppressors in acute myeloid leukemia

    DEFF Research Database (Denmark)

    Ge, Ying

    Acute myeloid leukemia (AML) is an aggressive malignancy characterized by uncontrolled expansion of immature myeloid cells in the hematopoietic tissues. Alternative splicing and epigenetic regulation are two mechanisms implicated in the pathogenesis of AML. In order to identify the essential...

  9. ERYTHEMA NODOSUM REVEALING ACUTE MYELOID LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Chebbi Wafa

    2013-07-01

    Full Text Available Introduction: Erythema nodosum (EN is the most common type of panniculitis. It may be idiopathic or secondary to various etiologies. However, the occurrence of erythema nodosum in malignant hemopathy had rarely been reported. Case report: A 42 year-old woman presented with a four week history of recurrent multiple painful erythematous nodules developed on the lower limbs associated with arthralgia of the ankles and fever. The clinical features of skin lesions with contusiform color evolution allowed establishing the diagnosis of EN. No underlying cause was found. The skin lesions were improved with non-steroidal anti-inflammatory drugs and colchicine. Three months later, the patient consulted for recurrence of EN associated with fever, inflammatory polyarthralgia and hepatosplenomegaly. The peripheral blood count revealed pancytopenia. A bone marrow examination confirmed the diagnosis of acute myeloid leukemia type 2. Initiation of chemotherapy was followed by the complete disappearance of skin lesions of EN. Conclusion: Paraneoplastic erythema nodosum is a rare entity. In the literature, a few cases of association with leukemia have been reported. Exploration for solid neoplasms or hemopathy in case of recurrent EN or resistance to conventional treatment should be systematic

  10. Myeloid Leukemia while on Dasatinib Therapy

    Directory of Open Access Journals (Sweden)

    Monika Conchon

    2010-01-01

    Full Text Available Here we report the case of an 18-year-old woman with chronic myeloid leukemia (CML who became pregnant while undergoing treatment with dasatinib. Before pregnancy, she received imatinib mesylate therapy but could not tolerate the treatment. The regimen was then changed to dasatinib at a dose of 70 mg b.i.d. While she was in hematological remission and on dasatinib therapy, she became pregnant. The unplanned pregnancy was identified after the patient had experienced four weeks of amenorrhea. Because the patient elected to continue the pregnancy to term, dasatinib was stopped immediately. Meanwhile, CML hematological relapse occurred and then she was treated with interferon- (IFN- (9 million IU/day throughout the pregnancy without a complete hematological response. She successfully gave birth to a male baby at 33 weeks by cesarean section delivery with no sequelae or malformations. Although this experience is limited to a single patient, it provides a useful contribution for counselling patients inadvertently exposed to dasatinib during pregnancy.

  11. Immunophenotypic investigation of infant acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    A. M. Popov

    2013-01-01

    Full Text Available Aim of the study – characterization of immunophenotype in infant acute myeloid leukemia (AML. 90 patients (40 boys and 50 girls with acute leukemia (AL aged up to 365 days were included in the current study. AML was found more frequently in infants than in older children (26.67 % and 10.83 % respectively; p = 0.0002. Significant immunophenotypic differences were observed in patients with and without MLL gene rearrangements. Number of cases in those tumor cells expressed CD99, CD61, CD133, CD15, NG2 varied between MLL-positive and MLL-negative groups. CD61-negativity, high CD99, CD15, CD133 and NG2 expression were immunophenotypic signatures of MLLrearranged infant AML, although CD99 and NG2 had the highest diagnostic efficacy. Thus infants’ AML immunophenotype differs significantly due to the presence of MLL gene rearrangements. Diagnostic immunophenotyping of infants’ AML allows predicting presence of MLL rearrangements by either CD99 or NG2 expression.

  12. Immunophenotypic investigation of infant acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    A. M. Popov

    2014-07-01

    Full Text Available Aim of the study – characterization of immunophenotype in infant acute myeloid leukemia (AML. 90 patients (40 boys and 50 girls with acute leukemia (AL aged up to 365 days were included in the current study. AML was found more frequently in infants than in older children (26.67 % and 10.83 % respectively; p = 0.0002. Significant immunophenotypic differences were observed in patients with and without MLL gene rearrangements. Number of cases in those tumor cells expressed CD99, CD61, CD133, CD15, NG2 varied between MLL-positive and MLL-negative groups. CD61-negativity, high CD99, CD15, CD133 and NG2 expression were immunophenotypic signatures of MLLrearranged infant AML, although CD99 and NG2 had the highest diagnostic efficacy. Thus infants’ AML immunophenotype differs significantly due to the presence of MLL gene rearrangements. Diagnostic immunophenotyping of infants’ AML allows predicting presence of MLL rearrangements by either CD99 or NG2 expression.

  13. An HSEF for murine myeloid leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Bond, V.P.; Cronkite, E.P.; Bullis, J.E. [Brookhaven National Lab., Upton, NY (United States); Wuu, C.S.; Marino, S.A.; Zaider, M. [Columbia Univ., New York, NY (United States). Dept. of Radiation Oncology

    1996-10-01

    In the past decade, a large amount of effort has gone into the development of hit size effectiveness functions (HSEFs), with the ultimate aim of replacing the present absorbed dose-RBE-Q system. However, the absorbed dose determined at the tissue level is incapable of providing information on single hits on (doses to) the single cell. As a result, it is necessary to resort to microdosimetry, which is capable of providing not only the number of hits on cells, but the distribution of hit sizes as well. From this information, an HSEF can be derived. However, to date there have been no sets of data available on animals exposed to radiations of several qualities, and for which microdosimetric data were available. The objective of the present set of experiments was to remedy this situation. Large numbers of mice were exposed to radiations of several different qualities, and were observed throughout their entire lifespan for the appearance of myeloid leukemia. The HSEF developed for this neoplasm is presented and discussed.

  14. An HSEF for murine myeloid leukemia

    International Nuclear Information System (INIS)

    Bond, V.P.; Cronkite, E.P.; Bullis, J.E.; Wuu, C.S.; Marino, S.A.; Zaider, M.

    1996-01-01

    In the past decade, a large amount of effort has gone into the development of hit size effectiveness functions (HSEFs), with the ultimate aim of replacing the present absorbed dose-RBE-Q system. However, the absorbed dose determined at the tissue level is incapable of providing information on single hits on (doses to) the single cell. As a result, it is necessary to resort to microdosimetry, which is capable of providing not only the number of hits on cells, but the distribution of hit sizes as well. From this information, an HSEF can be derived. However, to date there have been no sets of data available on animals exposed to radiations of several qualities, and for which microdosimetric data were available. The objective of the present set of experiments was to remedy this situation. Large numbers of mice were exposed to radiations of several different qualities, and were observed throughout their entire lifespan for the appearance of myeloid leukemia. The HSEF developed for this neoplasm is presented and discussed

  15. Optimized Treatment Schedules for Chronic Myeloid Leukemia.

    Directory of Open Access Journals (Sweden)

    Qie He

    2016-10-01

    Full Text Available Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib have been developed to treat Chronic Myeloid Leukemia (CML. Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies. However, the design of such combination therapies (timing, sequence, etc. remains an open challenge. In this work we mathematically model the dynamics of CML response to combination therapy and analyze the impact of combination treatment schedules on treatment efficacy in patients with preexisting resistance. We then propose an optimization problem to find the best schedule of multiple therapies based on the evolution of CML according to our ordinary differential equation model. This resulting optimization problem is nontrivial due to the presence of ordinary different equation constraints and integer variables. Our model also incorporates drug toxicity constraints by tracking the dynamics of patient neutrophil counts in response to therapy. We determine optimal combination strategies that maximize time until treatment failure on hypothetical patients, using parameters estimated from clinical data in the literature.

  16. Increased Power Capture by Rotor Speed–Dependent Yaw Control of Wind Turbines

    DEFF Research Database (Denmark)

    Kragh, Knud Abildgaard; Fleming, Paul A.; Scholbrock, Andrew K.

    2013-01-01

    the yaw alignment can be improved using measurements from the existing standard measurements system. By analyzing data from a case turbine and a corresponding meteorological mast, a correction scheme for the original yaw control system is suggested. The correction scheme is applied to the case turbine...... advanced measurement technologies, such as light detection and ranging systems. However, application of advanced measurement equipment is associated with additional costs and increased system complexity. This study is focused on assessing the current performance of an operating turbine and exploring how...

  17. Entrepreneurship education revisited: perceived entrepreneurial role models increase perceived behavioural control

    Science.gov (United States)

    Fellnhofer, Katharina

    2017-01-01

    Relying on Bandura’s (1986) social learning theory, Ajzen’s (1988) theory of planned behaviour (TPB), and Dyer’s (1994) model of entrepreneurial careers, this study aims to highlight the potential of entrepreneurial role models to entrepreneurship education. The results suggest that entrepreneurial courses would greatly benefit from real-life experiences, either positive or negative. The results of regression analysis based on 426 individuals, primarily from Austria, Finland, and Greece, show that role models increase learners’ entrepreneurial perceived behaviour control (PBC) by increasing their self-efficacy. This study can inform the research and business communities and governments about the importance of integrating entrepreneurs into education to stimulate entrepreneurial PBC. This study is the first of its kind using its approach, and its results warrant more in-depth studies of storytelling by entrepreneurial role models in the context of multimedia entrepreneurship education. PMID:29104604

  18. Entrepreneurship education revisited: perceived entrepreneurial role models increase perceived behavioural control.

    Science.gov (United States)

    Fellnhofer, Katharina

    2017-01-01

    Relying on Bandura's (1986) social learning theory, Ajzen's (1988) theory of planned behaviour (TPB), and Dyer's (1994) model of entrepreneurial careers, this study aims to highlight the potential of entrepreneurial role models to entrepreneurship education. The results suggest that entrepreneurial courses would greatly benefit from real-life experiences, either positive or negative. The results of regression analysis based on 426 individuals, primarily from Austria, Finland, and Greece, show that role models increase learners' entrepreneurial perceived behaviour control (PBC) by increasing their self-efficacy. This study can inform the research and business communities and governments about the importance of integrating entrepreneurs into education to stimulate entrepreneurial PBC. This study is the first of its kind using its approach, and its results warrant more in-depth studies of storytelling by entrepreneurial role models in the context of multimedia entrepreneurship education.

  19. An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia.

    Directory of Open Access Journals (Sweden)

    Sivakumar Periasamy

    2016-03-01

    Full Text Available Inhalation of Francisella tularensis (Ft causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection.

  20. An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia

    Science.gov (United States)

    Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda; MacNamara, Katherine C.; Sellati, Timothy J.; Harton, Jonathan A.

    2016-01-01

    Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection. PMID:27015566

  1. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia.

    Science.gov (United States)

    Baron, Jeffrey; Wang, Eunice S

    2018-06-11

    Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate consisting of a monoclonal antibody targeting CD33 linked to a cytotoxic derivative of calicheamicin. Despite the known clinical efficacy in relapsed/refractory acute myeloid leukemia (AML), GO was withdrawn from the market in 2010 due to increased early deaths witnessed in newly diagnosed AML patients receiving GO + intensive chemotherapy. In 2017, new data on the clinical efficacy and safety of GO administered on a fractionated-dosing schedule led to re-approval for newly diagnosed and relapsed/refractory AML. Areas covered: Addition of fractionated GO to chemotherapy significantly improved event-free survival of newly diagnosed AML patients with favorable and intermediate cytogenetic-risk disease. GO monotherapy also prolonged survival in newly diagnosed unfit patients and relapse-free survival in relapsed/refractory AML. This new dosing schedule was associated with decreased incidence of hepatotoxicity, veno-occlusive disease, and early mortality. Expert commentary: GO represents the first drug-antibody conjugate approved (twice) in the United States for AML. Its re-emergence adds a valuable agent back into the armamentarium for AML. The approval of GO as well as three other agents for AML in 2017 highlights the need for rapid cytogenetic and molecular characterization of AML and incorporation into new treatment algorithms.

  2. Current approach to the treatment of chronic myeloid leukaemia.

    Science.gov (United States)

    Pasic, Ivan; Lipton, Jeffrey H

    2017-04-01

    Of all the cancers, chronic myeloid leukaemia (CML) has witnessed the most rapid evolution of the therapeutic milieu in recent decades. The introduction of tyrosine kinase inhibitors (TKIs) as a therapeutic option has profoundly changed patient experience and outcome. The availability of multiple new highly effective therapies has increasingly underscored the importance of a good understanding of the underlying pathophysiological basis in CML, as well as patient-specific factors in choosing the right treatment for every individual. The treatment of CML has migrated in many jurisdictions from the office of a highly specialized malignant hematologist to the general hematologist or even a general practitioner. The goal of this review is to offer an overview of the modern approach to the treatment of CML, with an emphasis on chronic phase (CP) CML, including both TKI-based therapies such as imatinib, dasatinib, nilotinib, bosutinib and ponatinib, and non-TKI medications, such as omacetaxine. We discuss evidence behind each drug, most common and material adverse reactions and outline how this information can be used in selecting the right drug for the right patient. We also discuss evidence as it relates to other therapies, including stem cell transplant (SCT), and patients in accelerated (AP) and blastic phase (BP). Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. The genetic polymorphism and expression profiles of NLRP3 inflammasome in patients with chronic myeloid leukemia.

    Science.gov (United States)

    Zhang, Amin; Yu, Jie; Yan, Shuxin; Zhao, Xia; Chen, Chen; Zhou, Ying; Zhao, Xueyun; Hua, Mingqiang; Wang, Ruiqing; Zhang, Chen; Zhong, Chaoqin; He, Na; Ji, Chunyan; Ma, Daoxin

    2018-01-01

    NLRP3 inflammasome has been recently reported as an important risk factor in the development of cancer. But the relationship between polymorphisms of NLRP3 inflammasome related genes and chronic myeloid leukemia (CML) is rarely reported. Therefore, the aim of the present study was to investigate the association of five genetic polymorphisms (NLRP3, IL-1β, IL-18, CARD8 and NF-κB) in 267 CML patients and 344 healthy controls. We found that the AT genotype of CARD8 (rs2043211) was significantly higher compared to TT genotype in high and intermediate risk CML patients. IL-1β (rs16944) polymorphism in early molecular response at 6 months was marginally different, with more GG and less AA genotype in BCR-ABL IS >1% group. IL-18 (rs1946518) polymorphism was significantly different with more GG genotype in BCR-ABL IS >1% group at 6 months. We also demonstrated that WBC count of newly diagnosed patients carrying AG genotype was significantly higher than that of GG or AA genotype of IL-1β (rs16944). The onset age of patients carrying ins/ins genotype of NF-κB (rs28362491) was significantly older than that of ins/del and del/del genotype. Moreover, IL-1β or NLRP3 mRNA expression was decreased and IL-18 mRNA expression was increased significantly in CML patients compared with controls. In conclusion, the genetic polymorphisms of NLRP3 inflammasome may be served as potential predictors for CML. Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  4. Control costs, enhance quality, and increase revenue in three top general public hospitals in Beijing, China.

    Directory of Open Access Journals (Sweden)

    Lue-Ping Zhao

    Full Text Available BACKGROUND: With market-oriented economic and health-care reform, public hospitals in China have received unprecedented pressures from governmental regulations, public opinions, and financial demands. To adapt the changing environment and keep pace of modernizing healthcare delivery system, public hospitals in China are expanding clinical services and improving delivery efficiency, while controlling costs. Recent experiences are valuable lessons for guiding future healthcare reform. Here we carefully study three teaching hospitals, to exemplify their experiences during this period. METHODS: We performed a systematic analysis on hospitalization costs, health-care quality and delivery efficiencies from 2006 to 2010 in three teaching hospitals in Beijing, China. The analysis measured temporal changes of inpatient cost per stay (CPS, cost per day (CPD, inpatient mortality rate (IMR, and length of stay (LOS, using a generalized additive model. FINDINGS: There were 651,559 hospitalizations during the period analyzed. Averaged CPS was stable over time, while averaged CPD steadily increased by 41.7% (P<0.001, from CNY 1,531 in 2006 to CNY 2,169 in 2010. The increasing CPD seemed synchronous with the steady rising of the national annual income per capita. Surgical cost was the main contributor to the temporal change of CPD, while medicine and examination costs tended to be stable over time. From 2006 and 2010, IMR decreased by 36%, while LOS reduced by 25%. Increasing hospitalizations with higher costs, along with an overall stable CPS, reduced IMR, and shorter LOS, appear to be the major characteristics of these three hospitals at present. INTERPRETATIONS: These three teaching hospitals have gained some success in controlling costs, improving cares, adopting modern medical technologies, and increasing hospital revenues. Effective hospital governance and physicians' professional capacity plus government regulations and supervisions may have played a role

  5. Increasing patient involvement in the diabetic foot pathway: a pilot randomized controlled trial.

    Science.gov (United States)

    McBride, E; Hacking, B; O'Carroll, R; Young, M; Jahr, J; Borthwick, C; Callander, A; Berrada, Z

    2016-11-01

    This pilot study aimed to explore whether the use of an intervention to increase shared decision-making (Decision Navigation) increased decision self-efficacy and foot-treatment adherence in patients with a diabetic foot ulcer. Fifty-six patients with a diabetic foot ulcer were randomized to receive Decision Navigation (N = 30) or usual care (N = 26). Primary outcomes included decision self-efficacy, adherence to foot treatment as reported by the participant and adherence to foot treatment as reported by the clinician. Secondary outcomes included foot ulcer healing rate, health-related quality of life, decision conflict and decision regret. Despite participants rating Decision Navigation as very helpful, mixed analyses of variance revealed no differences in decision self-efficacy or adherence between those receiving Decision Navigation and those receiving usual care. There were no differences between groups with regards to the secondary outcomes, with the exception of decision conflict which increased over time (12 weeks) for those receiving Decision Navigation. An intervention that facilitated patient involvement in treatment decisions did not have any impact on decisional confidence or adherence to foot treatment. This does not provide support for the suggestion that personalized care can improve health-related outcomes at this progressed stage of the patient's disease trajectory. We suggest that the diabetic foot population may benefit from interventions aimed at increasing motivation to engage with care pathways, centred on challenging personal controllability beliefs. © 2016 Diabetes UK.

  6. Contribution of Co2+ in increasing chlorophyll a concentration of Nannochloropsis salina in controlled Conwy medium

    Science.gov (United States)

    Hala, Y.; Taba, P.; Suryati, E.; Kasih, P.; Firman, N. F.

    2018-03-01

    A research in determining the contribution of Co2+ on the increase of chlorophyll a concentration of Nannochloropsis salina has been caried out. The cultivation of N. salina was conducted in the Conwy medium with a salinity of 5%o and 25%o and various Co2+ concentration (2, 4, and 8 ppm). In this research, Co2+ was exposed early in the cultivation of N. salina. The growth of N. salina was observed daily by counting the number of populations using a haemocytometer while the chlorophyll a concentration was determined by a Uv-Vis spectrophotometer. The results showed that the growth of N. salina in the control was higher than that in the medium containing Co2+. The optimum growth time was achieved on 15th days (5%) and 8th days (25%). In the cultivation medium with a salinity of 5%, Co2+ with a concentration of 2 ppm increased the chlorophyll a level while Co2+ with concentrations of 4 and 8 ppm decreased it. In the medium of cultivation with a salinity of 25%, the increase in chlorophyll a level was observed at Co2+ concentrations of 2 and 4 ppm whereas the decrease in chlorophyl a level was given at a concentration of 8 ppm. It can be concluded that at low concentrations, Co2+ increased the concentration of chlorophyll a in N. salina.

  7. Increasing physical activity in patients with mental illness--A randomized controlled trial.

    Science.gov (United States)

    Göhner, Wiebke; Dietsche, Christine; Fuchs, Reinhard

    2015-11-01

    The objective of the study was to evaluate whether a motivational-volitional intervention program offered in addition to an existing sport program during stationary treatment is capable of establishing a post-stationary increase in physical activity in persons with mental illness. N=112 in-patients were initially randomly assigned to the control group (CG; standard rehabilitation) or intervention group (IG; standard rehabilitation plus intervention). Assessments were conducted at four measurement points. At 6 months follow up, the level of exercise in the IG was 95 min/week higher than in the CG (p=.02). The participants of the IG were able to increase their level of goal intention until 6 months follow up (t2: p=.03; t4: p=.005); levels of self-efficacy of the IG increased during intervention (t2: p=.001). Changes in volitional aspects were significant over time (t1-t3), but not specifically for the IG. The intervention was effective at increasing the level of physical activity in patients with mental illness who were initially minimally active. Our results suggest that it could be of great use to place the emphasis of a physical activity-enhancing intervention on its motivational effect since volitional aspects are already taken into sufficient account in standard rehabilitation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    Directory of Open Access Journals (Sweden)

    Mikael Bjursell

    Full Text Available Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1, the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  9. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    Science.gov (United States)

    Bjursell, Mikael; Wedin, Marianne; Admyre, Therése; Hermansson, Majlis; Böttcher, Gerhard; Göransson, Melker; Lindén, Daniel; Bamberg, Krister; Oscarsson, Jan; Bohlooly-Y, Mohammad

    2013-01-01

    Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  10. Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    Science.gov (United States)

    2018-02-16

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  11. Reversing the direction of galvanotaxis with controlled increases in boundary layer viscosity

    Science.gov (United States)

    Kobylkevich, Brian M.; Sarkar, Anyesha; Carlberg, Brady R.; Huang, Ling; Ranjit, Suman; Graham, David M.; Messerli, Mark A.

    2018-05-01

    Weak external electric fields (EFs) polarize cellular structure and direct most migrating cells (galvanotaxis) toward the cathode, making it a useful tool during tissue engineering and for healing epidermal wounds. However, the biophysical mechanisms for sensing weak EFs remain elusive. We have reinvestigated the mechanism of cathode-directed water flow (electro-osmosis) in the boundary layer of cells, by reducing it with neutral, viscous polymers. We report that increasing viscosity with low molecular weight polymers decreases cathodal migration and promotes anodal migration in a concentration dependent manner. In contrast, increased viscosity with high molecular weight polymers does not affect directionality. We explain the contradictory results in terms of porosity and hydraulic permeability between the polymers rather than in terms of bulk viscosity. These results provide the first evidence for controlled reversal of galvanotaxis using viscous agents and position the field closer to identifying the putative electric field receptor, a fundamental, outside-in signaling receptor that controls cellular polarity for different cell types.

  12. Control costs, enhance quality, and increase revenue in three top general public hospitals in Beijing, China.

    Science.gov (United States)

    Zhao, Lue-Ping; Yu, Guo-Pei; Liu, Hui; Ma, Xie-Min; Wang, Jing; Kong, Gui-Lan; Li, Yi; Ma, Wen; Cui, Yong; Xu, Beibei; Yu, Na; Bao, Xiao-Yuan; Guo, Yu; Wang, Fei; Zhang, Jun; Li, Yan; Xie, Xue-Qin; Jiang, Bao-Guo; Ke, Yang

    2013-01-01

    With market-oriented economic and health-care reform, public hospitals in China have received unprecedented pressures from governmental regulations, public opinions, and financial demands. To adapt the changing environment and keep pace of modernizing healthcare delivery system, public hospitals in China are expanding clinical services and improving delivery efficiency, while controlling costs. Recent experiences are valuable lessons for guiding future healthcare reform. Here we carefully study three teaching hospitals, to exemplify their experiences during this period. We performed a systematic analysis on hospitalization costs, health-care quality and delivery efficiencies from 2006 to 2010 in three teaching hospitals in Beijing, China. The analysis measured temporal changes of inpatient cost per stay (CPS), cost per day (CPD), inpatient mortality rate (IMR), and length of stay (LOS), using a generalized additive model. There were 651,559 hospitalizations during the period analyzed. Averaged CPS was stable over time, while averaged CPD steadily increased by 41.7% (Phospitalizations with higher costs, along with an overall stable CPS, reduced IMR, and shorter LOS, appear to be the major characteristics of these three hospitals at present. These three teaching hospitals have gained some success in controlling costs, improving cares, adopting modern medical technologies, and increasing hospital revenues. Effective hospital governance and physicians' professional capacity plus government regulations and supervisions may have played a role. However, purely market-oriented health-care reform could also misguide future healthcare reform.

  13. Water-filled training tubes increase core muscle activation and somatosensory control of balance during squat.

    Science.gov (United States)

    Ditroilo, Massimiliano; O'Sullivan, Rory; Harnan, Brian; Crossey, Aislinn; Gillmor, Beth; Dardis, William; Grainger, Adam

    2018-09-01

    This study examined trunk muscle activation, balance and proprioception while squatting with a water-filled training tube (WT) and a traditional barbell (BB), with either closed (CE) or open eyes (OE). Eighteen male elite Gaelic footballers performed an isometric squat under the following conditions: BB-OE, BB-CE, WT-OE and WT-CE. The activity of rectus abdominis (RA), external oblique (EO) and multifidus (MF) was measured using electromyography, along with sway of the centre of pressure (CoP) using a force platform. Only the EO and the MF muscles exhibited an increased activity with WT (p velocity and range of the CoP increased significantly with WT (p velocity of the CoP was marginally reduced (d = 0.29). WT elicited a greater level core muscle activation and created a greater challenge to postural stability when compared to a BB. It appears that WT does not benefit from vision but emphasises the somatosensory control of balance. The use of WT may be beneficial in those sports requiring development of somatosensory/proprioceptive contribution to balance control.

  14. Searching for control: priming randomness increases the evaluation of ritual efficacy.

    Science.gov (United States)

    Legare, Cristine H; Souza, André L

    2014-01-01

    Reestablishing feelings of control after experiencing uncertainty has long been considered a fundamental motive for human behavior. We propose that rituals (i.e., socially stipulated, causally opaque practices) provide a means for coping with the aversive feelings associated with randomness due to the perception of a connection between ritual action and a desired outcome. Two experiments were conducted (one in Brazil [n = 40] and another in the United States [n = 94]) to evaluate how the perceived efficacy of rituals is affected by feelings of randomness. In a between-subjects design, the Scramble Sentence Task was used as a priming procedure in three conditions (i.e., randomness, negativity, and neutral) and participants were then asked to rate the efficacy of rituals used for problem-solving purposes. The results demonstrate that priming randomness increased participants' perception of ritual efficacy relative to negativity and neutral conditions. Implications for increasing our understanding of the relationship between perceived control and ritualistic behavior are discussed. Copyright © 2013 Cognitive Science Society, Inc.

  15. Taking control: Working memory training in overweight individuals increases self-regulation of food intake.

    Science.gov (United States)

    Houben, Katrijn; Dassen, Fania C M; Jansen, Anita

    2016-10-01

    Working memory (WM) plays a critical role in cognitive control by shielding self-regulatory goals from distraction by desire-related thoughts and emotions. This study examined whether training WM increases self-regulation in overweight participants. It was hypothesized that WM training would decrease psychopathological eating-related thoughts, (over)consumption of food in response to emotions and external cues, food intake and body weight. Overweight participants (n = 50) performed 20-25 sessions of WM training or control/sham training. The dependent measures were self-reported eating-related psychopathology, self-reported emotional/external eating behavior, food intake during a bogus taste test, and body weight, assessed before training, immediately following training, and at one-month follow-up. Relative to control, WM training reduced psychopathological eating-related thoughts and emotional eating (but not external eating). These effects were still present at follow-up, one month later. Food intake and body weight did not show an overall effect of training, though WM training did reduce food intake among highly restrained participants. WM training effectively reduced eating-related thoughts, overeating in response to negative emotions, and food intake among participants with strong dietary restraint goals. Hence, these findings indicate that WM training may strengthen self-regulation by shielding dieting goals from distraction by unwanted eating-related thoughts and emotions. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Framing Financial Incentives to Increase Physical Activity Among Overweight and Obese Adults: A Randomized, Controlled Trial.

    Science.gov (United States)

    Patel, Mitesh S; Asch, David A; Rosin, Roy; Small, Dylan S; Bellamy, Scarlett L; Heuer, Jack; Sproat, Susan; Hyson, Chris; Haff, Nancy; Lee, Samantha M; Wesby, Lisa; Hoffer, Karen; Shuttleworth, David; Taylor, Devon H; Hilbert, Victoria; Zhu, Jingsan; Yang, Lin; Wang, Xingmei; Volpp, Kevin G

    2016-03-15

    Financial incentive designs to increase physical activity have not been well-examined. To test the effectiveness of 3 methods to frame financial incentives to increase physical activity among overweight and obese adults. Randomized, controlled trial. (ClinicalTrials.gov: NCT 02030119). University of Pennsylvania. 281 adult employees (body mass index ≥27 kg/m2). 13-week intervention. Participants had a goal of 7000 steps per day and were randomly assigned to a control group with daily feedback or 1 of 3 financial incentive programs with daily feedback: a gain incentive ($1.40 given each day the goal was achieved), lottery incentive (daily eligibility [expected value approximately $1.40] if goal was achieved), or loss incentive ($42 allocated monthly upfront and $1.40 removed each day the goal was not achieved). Participants were followed for another 13 weeks with daily performance feedback but no incentives. Primary outcome was the mean proportion of participant-days that the 7000-step goal was achieved during the intervention. Secondary outcomes included the mean proportion of participant-days achieving the goal during follow-up and the mean daily steps during intervention and follow-up. The mean proportion of participant-days achieving the goal was 0.30 (95% CI, 0.22 to 0.37) in the control group, 0.35 (CI, 0.28 to 0.42) in the gain-incentive group, 0.36 (CI, 0.29 to 0.43) in the lottery-incentive group, and 0.45 (CI, 0.38 to 0.52) in the loss-incentive group. In adjusted analyses, only the loss-incentive group had a significantly greater mean proportion of participant-days achieving the goal than control (adjusted difference, 0.16 [CI, 0.06 to 0.26]; P = 0.001), but the adjusted difference in mean daily steps was not significant (861 [CI, 24 to 1746]; P = 0.056). During follow-up, daily steps decreased for all incentive groups and were not different from control. Single employer. Financial incentives framed as a loss were most effective for achieving physical

  17. Increasing Physical Activity in Mothers Using Video Exercise Groups and Exercise Mobile Apps: Randomized Controlled Trial.

    Science.gov (United States)

    Mascarenhas, Maya Nina; Chan, June Maylin; Vittinghoff, Eric; Van Blarigan, Erin Lynn; Hecht, Frederick

    2018-05-18

    Women significantly decrease their activity levels in the transition to motherhood. Digital health technologies are low cost, scalable, and can provide an effective delivery mechanism for behavior change. This is the first study that examines the use of videoconferencing and mobile apps to create exercise groups for mothers. The aim of the study was to test the feasibility, acceptability, and effectiveness of an individually adaptive and socially supportive physical activity intervention incorporating videoconferencing and mobile apps for mothers. The Moms Online Video Exercise Study was an 8-week, 2-armed, Web-based randomized trial comparing the effectiveness of a group exercise intervention with a waitlist control. Healthy mothers with at least 1 child under the age of 12 years were recruited through Facebook and email listservs. Intervention participants joined exercise groups using videoconferencing (Google Hangouts) every morning on weekdays and exercised together in real time, guided by exercise mobile apps (eg, Nike+, Sworkit) of their choice. Waitlist control participants had access to recommended mobile apps and an invitation to join an exercise group after the 8-week study period. Main outcomes assessed included changes in self-reported moderate, vigorous, and moderate to vigorous physical activity (MVPA) minutes per week in aggregate and stratified by whether women met Centers for Disease Control and Prevention guidelines for sufficient aerobic activity at baseline. Outcomes were measured through self-assessed Web-based questionnaires at baseline and 8 weeks. The intervention was effective at increasing exercise for inactive women and proved to be feasible and acceptable to all participants. A total of 64 women were randomized, 30 to intervention and 34 to control. Women attended 2.8 sessions per week. There was a strong, but not statistically significant, trend toward increasing moderate, vigorous, and MVPA minutes for all women. As hypothesized, in

  18. Support or competition? How online social networks increase physical activity: A randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Jingwen Zhang, PhD

    2016-12-01

    Full Text Available To identify what features of online social networks can increase physical activity, we conducted a 4-arm randomized controlled trial in 2014 in Philadelphia, PA. Students (n = 790, mean age = 25.2 at an university were randomly assigned to one of four conditions composed of either supportive or competitive relationships and either with individual or team incentives for attending exercise classes. The social comparison condition placed participants into 6-person competitive networks with individual incentives. The social support condition placed participants into 6-person teams with team incentives. The combined condition with both supportive and competitive relationships placed participants into 6-person teams, where participants could compare their team's performance to 5 other teams' performances. The control condition only allowed participants to attend classes with individual incentives. Rewards were based on the total number of classes attended by an individual, or the average number of classes attended by the members of a team. The outcome was the number of classes that participants attended. Data were analyzed using multilevel models in 2014. The mean attendance numbers per week were 35.7, 38.5, 20.3, and 16.8 in the social comparison, the combined, the control, and the social support conditions. Attendance numbers were 90% higher in the social comparison and the combined conditions (mean = 1.9, SE = 0.2 in contrast to the two conditions without comparison (mean = 1.0, SE = 0.2 (p = 0.003. Social comparison was more effective for increasing physical activity than social support and its effects did not depend on individual or team incentives.

  19. Increased efficiency in the second-hand tire trade provides opportunity for dengue control.

    Science.gov (United States)

    Pliego Pliego, Emilene; Velázquez-Castro, Jorge; Eichhorn, Markus P; Fraguela Collar, Andrés

    2018-01-21

    Dengue fever is increasing in geographical range, spread by invasion of its vector mosquitoes. The trade in second-hand tires has been implicated as a factor in this process because they act as mobile reservoirs of mosquito eggs and larvae. Regional transportation of tires can create linkages between rural areas with dengue and disease-free urban areas, potentially giving rise to outbreaks even in areas with strong local control measures. In this work we sought to model the dynamics of mosquito transportation via the tire trade, in particular to predict its role in causing unexpected dengue outbreaks through vertical transmission of the virus across generations of mosquitoes. We also aimed to identify strategies for regulating the trade in second-hand tires, improving disease control. We created a mathematical model which captures the dynamics of dengue between rural and urban areas, taking into account the movement and storage time of tires, and mosquito diapause. We simulate a series of scenarios in which a mosquito population is introduced to a dengue-free area via movement of tires, either as single or multiple events, increasing the likelihood of a dengue outbreak. A persistent disease state can be induced regardless of whether urban conditions for an outbreak are met, and an existing endemic state can be enhanced by vector input. Finally we assess the potential for regulation of tire processing as a means of reducing the transmission of dengue fever using a specific case study from Puerto Rico. Our work demonstrates the importance of the second-hand tire trade in modulating the spread of dengue fever across regions, in particular its role in introducing dengue to disease-free areas. We propose that reduction of tire storage time and control of their movement can play a crucial role in containing dengue outbreaks. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Splenectomy correlates with increased risk of pulmonary tuberculosis: a case-control study in Taiwan.

    Science.gov (United States)

    Lai, S-W; Wang, I-K; Lin, C-L; Chen, H-J; Liao, K-F

    2014-08-01

    This study investigated whether there was an association between splenectomy and pulmonary tuberculosis. This was a case-control study using the database of the Taiwan National Health Insurance Programme. We identified 18 960 patients (aged 20 years or older) with newly diagnosed pulmonary tuberculosis as the case group and 73 988 participants without pulmonary tuberculosis as the control group from 1998 to 2011. Both groups were matched for sex, age (per 5 years) and index year of pulmonary tuberculosis diagnosis. The risk of pulmonary tuberculosis associated with splenectomy and other co-morbidities was estimated. After controlling for confounders, multivariable logistic regression analysis showed that the odds of pulmonary tuberculosis were 1.91 in patients with splenectomy (95% CI 1.06-3.44), compared with the participants without splenectomy. Chronic obstructive pulmonary diseases (OR 3.07, 95% CI 2.94-3.21), pneumoconiosis (OR 2.20, 95% CI 1.90-2.56), chronic kidney diseases (OR 1.49, 95% CI 1.33-1.67), diabetes mellitus (OR 1.57, 95% CI 1.50-1.64) and chronic liver diseases (OR 1.31, 95% CI 1.25-1.37) were associated with an increased risk of pulmonary tuberculosis. The sub-analysis demonstrated that the odds of pulmonary tuberculosis were 4.81 (95% CI 2.31-10.0) for patients co-morbid with splenectomy and any of the above diseases. Splenectomy is associated with a 1.9-fold increased risk of pulmonary tuberculosis in Taiwan. There is a synergistic effect between splenectomy and other co-morbidities on the risk of pulmonary tuberculosis. © 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

  1. Short-term myeloid growth factor mediated expansion of bone marrow haemopoiesis studied by localized magnetic resonance proton spectroscopy

    DEFF Research Database (Denmark)

    Jensen, K E; Hansen, P B; Larsen, V A

    1994-01-01

    -density cell proliferation rate in marrow samples increased from median 21.9 (range 4.5-31) x 10(3) cpm to 54.7 (range 13.9-94) x 10(3) cpm and the total number of myeloid progenitors enumerated as day 7/14 GM-CFUs per volume aspirated marrow increased from median 11/8 x 10(3) (range 4.0-87.5/2.2-103.0) to 64...

  2. Identification of myeloid derived suppressor cells in the peripheral blood of tumor bearing dogs

    Directory of Open Access Journals (Sweden)

    Sherger Matthew

    2012-10-01

    Full Text Available Abstract Background Myeloid derived suppressor cells (MDSCs are a recently described population of immune cells that significantly contribute to the immunosuppression seen in cancer patients. MDSCs are one of the most important factors that limit the efficacy of cancer immunotherapy (e.g. cancer vaccines and MDSC levels are increased in cancer in multiple species. Identifying and targeting MDSCs is actively being investigated in the field of human oncology and is increasingly being investigated in veterinary oncology. The treatment of canine cancer not only benefits dogs, but is being used for translational studies evaluating and modifcying candidate therapies for use in humans. Thus, it is necessary to understand the immune alterations seen in canine cancer patients which, to date, have been relatively limited. This study investigates the use of commercially available canine antibodies to detect an immunosuppressive (CD11blow/CADO48low cell population that is increased in the peripheral blood of tumor-bearing dogs. Results Commercially available canine antibodies CD11b and CADO48A were used to evaluate white blood cells from the peripheral blood cells of forty healthy control dogs and forty untreated, tumor-bearing dogs. Tumor-bearing dogs had a statistically significant increase in CD11blow/CADO48Alow cells (7.9% as compared to the control dogs (3.6%. Additionally, sorted CD11blow/CADO48Alow generated in vitro suppressed the proliferation of canine lymphocytes. Conclusions The purpose of this study was aimed at identifying potential canine specific markers for identifying MDSCs in the peripheral blood circulation of dogs. This study demonstrates an increase in a unique CD11blow/CADO48Alow cell population in tumor-bearing dogs. This immunophenotype is consistent with described phenotypes of MDSCs in other species (i.e. mice and utilizes commercially available canine-specific antibodies. Importantly, CD11blow/CADO48Alow from a tumor environment

  3. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).

    Science.gov (United States)

    Goodyear, Oliver C; Dennis, Mike; Jilani, Nadira Y; Loke, Justin; Siddique, Shamyla; Ryan, Gordon; Nunnick, Jane; Khanum, Rahela; Raghavan, Manoj; Cook, Mark; Snowden, John A; Griffiths, Mike; Russell, Nigel; Yin, John; Crawley, Charles; Cook, Gordon; Vyas, Paresh; Moss, Paul; Malladi, Ram; Craddock, Charles F

    2012-04-05

    Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.

  4. Deferasirox and vitamin D improves overall survival in elderly patients with acute myeloid leukemia after demethylating agents failure.

    Directory of Open Access Journals (Sweden)

    Etienne Paubelle

    Full Text Available The prognosis of acute myeloid leukemia (AML in elderly (≥65 years patients is poor and treatment remains non-consensual especially for those who are not eligible for intensive therapies. Our group has shown that in vitro the iron chelator deferasirox (DFX synergizes with vitamin D (VD to promote monocyte differentiation in primary AML cells. Herein, we present results from a retrospective case-control study in which the association of DFX (1-2 g/d and 25-hydroxycholecalciferol (100,000 IU/week (DFX/VD was proposed to patients following demethylating agents failure. Median survival of patients treated with DFX/VD combination (n = 17 was significantly increased in comparison with matched patients receiving best supportive care (BSC alone (n = 13 (10.4 versus 4 months respectively. In addition, the only factor associated to an increased overall survival in DFX/VD-treated patients was serum VD levels. We conclude that DFX/VD treatment correlated with increased overall survival of AML patients in this retrospective cohort of elderly patients.

  5. Do Instructional Videos on Sputum Submission Result in Increased Tuberculosis Case Detection? A Randomized Controlled Trial.

    Science.gov (United States)

    Mhalu, Grace; Hella, Jerry; Doulla, Basra; Mhimbira, Francis; Mtutu, Hawa; Hiza, Helen; Sasamalo, Mohamed; Rutaihwa, Liliana; Rieder, Hans L; Seimon, Tamsyn; Mutayoba, Beatrice; Weiss, Mitchell G; Fenner, Lukas

    2015-01-01

    We examined the effect of an instructional video about the production of diagnostic sputum on case detection of tuberculosis (TB), and evaluated the acceptance of the video. Randomized controlled trial. We prepared a culturally adapted instructional video for sputum submission. We analyzed 200 presumptive TB cases coughing for more than two weeks who attended the outpatient department of the governmental Municipal Hospital in Mwananyamala (Dar es Salaam, Tanzania). They were randomly assigned to either receive instructions on sputum submission using the video before submission (intervention group, n = 100) or standard of care (control group, n = 100). Sputum samples were examined for volume, quality and presence of acid-fast bacilli by experienced laboratory technicians blinded to study groups. Median age was 39.1 years (interquartile range 37.0-50.0); 94 (47%) were females, 106 (53%) were males, and 49 (24.5%) were HIV-infected. We found that the instructional video intervention was associated with detection of a higher proportion of microscopically confirmed cases (56%, 95% confidence interval [95% CI] 45.7-65.9%, sputum smear positive patients in the intervention group versus 23%, 95% CI 15.2-32.5%, in the control group, p sex, modified the effectiveness of the intervention by improving it positively. When asked how well the video instructions were understood, the majority of patients in the intervention group reported to have understood the video instructions well (97%). Most of the patients thought the video would be useful in the cultural setting of Tanzania (92%). Sputum submission instructional videos increased the yield of tuberculosis cases through better quality of sputum samples. If confirmed in larger studies, instructional videos may have a substantial effect on the case yield using sputum microscopy and also molecular tests. This low-cost strategy should be considered as part of the efforts to control TB in resource-limited settings. Pan African

  6. A randomized, controlled trial to increase discussion of breast cancer in primary care.

    Science.gov (United States)

    Kaplan, Celia P; Livaudais-Toman, Jennifer; Tice, Jeffrey A; Kerlikowske, Karla; Gregorich, Steven E; Pérez-Stable, Eliseo J; Pasick, Rena J; Chen, Alice; Quinn, Jessica; Karliner, Leah S

    2014-07-01

    Assessment and discussion of individual risk for breast cancer within the primary care setting are crucial to discussion of risk reduction and timely referral. We conducted a randomized controlled trial of a multiethnic, multilingual sample of women ages 40 to 74 years from two primary care practices (one academic, one safety net) to test a breast cancer risk assessment and education intervention. Patients were randomly assigned to control or intervention group. All patients completed a baseline telephone survey and risk assessment (via telephone for controls, via tablet computer in clinic waiting room before visit for intervention). Intervention (BreastCARE) patients and their physicians received an individualized risk report to discuss during the visit. One-week follow-up telephone surveys with all patients assessed patient-physician discussion of family cancer history, personal breast cancer risk, high-risk clinics, and genetic counseling/testing. A total of 655 control and 580 intervention women completed the risk assessment and follow-up interview; 25% were high-risk by family history, Gail, or Breast Cancer Surveillance Consortium risk models. BreastCARE increased discussions of family cancer history [OR, 1.54; 95% confidence interval (CI), 1.25-1.91], personal breast cancer risk (OR, 4.15; 95% CI, 3.02-5.70), high-risk clinics (OR, 3.84; 95% CI, 2.13-6.95), and genetic counseling/testing (OR, 2.22; 95% CI, 1.34-3.68). Among high-risk women, all intervention effects were stronger. An intervention combining an easy-to-use, quick risk assessment tool with patient-centered risk reports at the point of care can successfully promote discussion of breast cancer risk reduction between patients and primary care physicians, particularly for high-risk women. Next steps include scaling and dissemination of BreastCARE with integration into electronic medical record systems. ©2014 American Association for Cancer Research.

  7. High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

    Science.gov (United States)

    Zeng, Zhihong; Liu, Wenbin; Tsao, Twee; Qiu, YiHua; Zhao, Yang; Samudio, Ismael; Sarbassov, Dos D; Kornblau, Steven M; Baggerly, Keith A; Kantarjian, Hagop M; Konopleva, Marina; Andreeff, Michael

    2017-09-01

    The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse-phase protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment. Stroma reprogrammed signaling networks and modified the sensitivity of acute myeloid leukemia samples to all three targeted inhibitors. Stroma activated AKT at Ser473 in the majority of samples treated with single-agent ABT737 or Nutlin-3a. This survival mechanism was partially abrogated by concomitant treatment with temsirolimus plus ABT737 or Nutlin-3a. Mapping the signaling networks revealed that combinations of two inhibitors increased the number of affected proteins in the targeted pathways and in multiple parallel signaling, translating into facilitated cell death. These results demonstrated that a mechanism-based selection of combined inhibitors can be used to guide clinical drug selection and tailor treatment regimens to eliminate microenvironment-mediated resistance in acute myeloid leukemia. Copyright© 2017 Ferrata Storti Foundation.

  8. Lower extremity fatigue increases complexity of postural control during a single-legged stance

    Directory of Open Access Journals (Sweden)

    Bailey Jerry J

    2011-08-01

    Full Text Available Abstract Background Non-linear approaches to assessment of postural control can provide insight that compliment linear approaches. Control entropy (CE is a recently developed statistical tool from non-linear dynamical systems used to assess the complexity of non-stationary signals. We have previously used CE of high resolution accelerometry in running to show decreased complexity with exhaustive exercise. The purpose of this study was to determine if complexity of postural control decreases following fatiguing exercise using CE. Methods Ten subjects (5 M/5 F; 25 ± 3 yr; 169.4 ± 11.7 cm; 79.0 ± 16.9 kg consented to participation approved by Western Oregon University IRB and completed two trials separated by 2-7 days. Trials consisted of two single-legged balance tests separated by two Wingate anaerobic tests (WAnT; PreFat/PostFat, or rest period (PreRest/PostRest. Balance tests consisted of a series of five single-legged stances, separated by 30 s rest, performed while standing on the dominant leg for 15-s with the participant crossing the arms over the chest and flexing the non-dominant knee to 90 degrees. High resolution accelerometers (HRA were fixed superficial to L3/L4 at the approximate center of mass (COM. Triaxial signals from the HRA were streamed in real time at 625 Hz. COM accelerations were recorded in g's for vertical (VT, medial/lateral (ML, and anterior/posterior (AP axes. A newly developed statistic (R-test was applied to group response shapes generated by Karhunen Loeve (KL transform modes resulting from Control Entropy (CE analysis. Results R-tests showed a significant mean vector difference (p p p p Conclusions These data indicate that fatiguing exercise eliminates the differential complexity response between axes, but increases complexity in all axes compared to the non-fatigued condition. This has implications with regard to the effects of fatigue on strategies of the control system to maintain postural control.

  9. A stratified myeloid system, the challenge of understanding macrophage diversity.

    Science.gov (United States)

    Geissmann, F; Mass, E

    2015-12-01

    The present issue of 'Seminars in Immunology' addresses the topic of macrophage biology, 100 years after the death of Elie Metchnikoff (May 1845-July 1916). As foreseen by Metchnikoff, the roles of macrophages in the maintenance of homeostasis and immunity against pathogens have become a broad and active area of investigation. We now start to realize that the myeloid system includes a multiplicity of cell types with diverse developmental origins and functions. Therefore, the textbook picture of a plastic and multifunctional macrophage does not meet the requirements of our current knowledge anymore. Further development toward a quantitative and molecular understanding of myeloid cell biology in vivo and their roles in tissue homeostasis and remodeling will benefit from taking this complexity into account. A tentative model to help in this pursuit and account for myeloid cell and macrophage diversity is discussed below. Copyright © 2016. Published by Elsevier Ltd.

  10. Acute myeloid leukemia in the era of precision medicine: recent advances in diagnostic classification and risk stratification

    International Nuclear Information System (INIS)

    Kansal, Rina

    2016-01-01

    Acute myeloid leukemia (AML) is a genetically heterogeneous myeloid malignancy that occurs more commonly in adults, and has an increasing incidence, most likely due to increasing age. Precise diagnostic classification of AML requires clinical and pathologic information, the latter including morphologic, immunophenotypic, cytogenetic and molecular genetic analysis. Risk stratification in AML requires cytogenetics evaluation as the most important predictor, with genetic mutations providing additional necessary information. AML with normal cytogenetics comprises about 40%-50% of all AML, and has been intensively investigated. The currently used 2008 World Health Organization classification of hematopoietic neoplasms has been proposed to be updated in 2016, also to include an update on the classification of AML, due to the continuously increasing application of genomic techniques that have led to major advances in our knowledge of the pathogenesis of AML. The purpose of this review is to describe some of these recent major advances in the diagnostic classification and risk stratification of AML

  11. Acute myeloid leukemia in the era of precision medicine: recent advances in diagnostic classification and risk stratification.

    Science.gov (United States)

    Kansal, Rina

    2016-03-01

    Acute myeloid leukemia (AML) is a genetically heterogeneous myeloid malignancy that occurs more commonly in adults, and has an increasing incidence, most likely due to increasing age. Precise diagnostic classification of AML requires clinical and pathologic information, the latter including morphologic, immunophenotypic, cytogenetic and molecular genetic analysis. Risk stratification in AML requires cytogenetics evaluation as the most important predictor, with genetic mutations providing additional necessary information. AML with normal cytogenetics comprises about 40%-50% of all AML, and has been intensively investigated. The currently used 2008 World Health Organization classification of hematopoietic neoplasms has been proposed to be updated in 2016, also to include an update on the classification of AML, due to the continuously increasing application of genomic techniques that have led to major advances in our knowledge of the pathogenesis of AML. The purpose of this review is to describe some of these recent major advances in the diagnostic classification and risk stratification of AML.

  12. Do Instructional Videos on Sputum Submission Result in Increased Tuberculosis Case Detection? A Randomized Controlled Trial.

    Directory of Open Access Journals (Sweden)

    Grace Mhalu

    Full Text Available We examined the effect of an instructional video about the production of diagnostic sputum on case detection of tuberculosis (TB, and evaluated the acceptance of the video.Randomized controlled trial.We prepared a culturally adapted instructional video for sputum submission. We analyzed 200 presumptive TB cases coughing for more than two weeks who attended the outpatient department of the governmental Municipal Hospital in Mwananyamala (Dar es Salaam, Tanzania. They were randomly assigned to either receive instructions on sputum submission using the video before submission (intervention group, n = 100 or standard of care (control group, n = 100. Sputum samples were examined for volume, quality and presence of acid-fast bacilli by experienced laboratory technicians blinded to study groups.Median age was 39.1 years (interquartile range 37.0-50.0; 94 (47% were females, 106 (53% were males, and 49 (24.5% were HIV-infected. We found that the instructional video intervention was associated with detection of a higher proportion of microscopically confirmed cases (56%, 95% confidence interval [95% CI] 45.7-65.9%, sputum smear positive patients in the intervention group versus 23%, 95% CI 15.2-32.5%, in the control group, p <0.0001, an increase in volume of specimen defined as a volume ≥3ml (78%, 95% CI 68.6-85.7%, versus 45%, 95% CI 35.0-55.3%, p <0.0001, and specimens less likely to be salivary (14%, 95% CI 7.9-22.4%, versus 39%, 95% CI 29.4-49.3%, p = 0.0001. Older age, but not the HIV status or sex, modified the effectiveness of the intervention by improving it positively. When asked how well the video instructions were understood, the majority of patients in the intervention group reported to have understood the video instructions well (97%. Most of the patients thought the video would be useful in the cultural setting of Tanzania (92%.Sputum submission instructional videos increased the yield of tuberculosis cases through better quality of sputum

  13. Additional chromosome abnormalities in chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Hui-Hua Hsiao

    2011-02-01

    Full Text Available The Philadelphia (Ph chromosome and/or Breakpoint cluster region-Abelson leukemia virus oncogene transcript are unique markers for chronic myeloid leukemia (CML. However, CML demonstrates heterogeneous presentations and outcomes. We analyzed the cytogenetic and molecular results of CML patients to evaluate their correlation with clinical presentations and outcome. A total of 84 newly diagnosed CML patients were enrolled in the study. Patients were treated according to disease status. Bone marrow samples were obtained to perform cytogenetic and molecular studies. Clinical presentations, treatment courses, and survival were reviewed retrospectively. Among 84 patients, 72 had chronic phase and 12 had accelerated phase CML. Cytogenetic study showed 69 (82.1% with the classic Ph chromosome, 6 (7.2% with a variant Ph chromosome, and 9 (10.7% with additional chromosome abnormalities. Fifty-four (64.3% cases harbored b3a2 transcripts, 29 (34.5% had b2a2 transcript, and 1 had e19a2 transcript. There was no difference in clinical presentations between different cytogenetic and molecular groups; however, additional chromosome abnormalities were significantly associated with the accelerated phase. Imatinib therapy was an effective treatment, as measured by cytogenetic response, when administered as first- and second-line therapy in chronic phase patients. Survival analysis showed that old age, additional chromosome abnormalities, high Sokal score, and no cytogenetic response in second-line therapy had a significant poor impact (p<0.05. In conclusion, we presented the cytogenetic and molecular pattern of CML patients and demonstrated that the additional chromosome abnormality was associated with poor outcome.

  14. Local sharing of cogeneration energy through individually prioritized controls for increased on-site energy utilization

    International Nuclear Information System (INIS)

    Hirvonen, Janne; Kayo, Genku; Hasan, Ala; Sirén, Kai

    2014-01-01

    Highlights: • Sharing of surplus heat and electricity produced by CHP plants in different types of buildings. • Individually prioritized control of CHP plants with direct local sharing and minimal storage capacity. • Energy sharing reduced primary energy consumption by 1–9% with biogas. • Excess energy minimized by thermal tracking. - Abstract: All over the world, including Japan, there are targets to decrease building energy consumption and increase renewable energy utilization. Combined heat and power (CHP) plants increase energy efficiency and are becoming popular in Japan. CHP plants produce both heat and power simultaneously, but there is not always a need for both. A cluster of several different buildings can increase total efficiency and reduce primary energy (PE) consumption by sharing excess heat and electricity between neighboring buildings. If the generated energy comes from renewable sources, energy sharing makes it easier to reach the net zero energy balance. By adjusting CHP sizes and operation patterns, the wasted heat and primary energy consumption can be minimized. Energy sharing has been explored in situations with identical buildings and centrally administered energy systems before, but not with different building types with separate systems. In this study, a cluster of Japanese office and residential buildings were combined to allow heat and electricity sharing based on cogeneration, using individually prioritized control (IPC) systems. TRNSYS simulation was used to match energy generation with pregenerated demand profiles. Absorption cooling was utilized to increase the benefits of local heat generation. Different CHP operation modes and plant sizes were tested. The benefit of surplus energy sharing depends on the CHP capacities and the fuel type. When using biogas, larger CHP plants provided lower total primary energy consumption, in the most extreme case lowering it by 71%, compared to the conventional case. Using natural gas

  15. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Saglio, Giuseppe; Kim, Dong-Wook; Issaragrisil, Surapol

    2010-01-01

    Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.......Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase....

  16. Applied means to increase stimulation in the control room work at the Swedish nuclear power plants

    International Nuclear Information System (INIS)

    Blomberg, P.E.; Akerhielm, F.

    1988-01-01

    Nuclear power plants are generally designed and built with a quality which implies that the units seldom require intervention from the operating staff under normal operating conditions. This leaves the operators with the dominating task of only passively supervising the process. A number of measures have been taken to counteract the problem of under-stimulated individuals in the control rooms and to maintain active and purposeful working conditions. Basically these measures derive from the belief that augmented competence, increased responsibilities and a enhanced sense of indispensability functions as an inspiration even in a monotonous working situation. For this purpose a number of activities and tasks, parallel to the normal duties as member of the operating staff, have been implemented

  17. INCREASING OF ECOLOGICAL EFFICIENCY OF WORN EQUIPMENT BY PARTIAL UPDATES. ANALYTICAL AND CONTROL ASPECT

    Directory of Open Access Journals (Sweden)

    S. Voinova

    2017-12-01

    Full Text Available The current state of worn industrial equipment and the resulting low performance indicators of its functioning, in particular, low environmental friendliness, are considered. It is shown that the normalization of the complex situation that has developed in production is an acute problem, the solution of which should begin with the implementation of a program for the partial renewal of worn equipment. It is pointed out that there is a high potential for improving the technological, including ecological, efficiency of functioning of the upgraded equipment. It is pointed out that the partial renewal is highly efficient, because of the small specific investments in it. The significant influence of the quality of control of the setting and implementation of the renewal program on its effectiveness was noted. It is shown that the process of renewal of worn-out equipment, ultimately, has an environmental focus, increases the environmental friendliness of the updated technical facility.

  18. Increased cognitive control after task conflict? Investigating the N-3 effect in task switching.

    Science.gov (United States)

    Schuch, Stefanie; Grange, James A

    2018-05-25

    Task inhibition is considered to facilitate switching to a new task and is assumed to decay slowly over time. Hence, more persisting inhibition needs to be overcome when returning to a task after one intermediary trial (ABA task sequence) than when returning after two or more intermediary trials (CBA task sequence). Schuch and Grange (J Exp Psychol Learn Mem Cogn 41:760-767, 2015) put forward the hypothesis that there is higher task conflict in ABA than CBA sequences, leading to increased cognitive control in the subsequent trial. They provided evidence that performance is better in trials following ABA than following CBA task sequences. Here, this effect of the previous task sequence ("N-3 effect") is further investigated by varying the cue-stimulus interval (CSI), allowing for short (100 ms) or long (900 ms) preparation time for the upcoming task. If increased cognitive control after ABA involves a better preparation for the upcoming task, the N-3 effect should be larger with long than short CSI. The results clearly show that this is not the case. In Experiment 1, the N-3 effect was smaller with long than short CSI; in Experiment 2, the N-3 effect was not affected by CSI. Diffusion model analysis confirmed previous results in the literature (regarding the effect of CSI and of the ABA-CBA difference); however, the N-3 effect was not unequivocally associated with any of the diffusion model parameters. In exploratory analysis, we also tested the alternative hypothesis that the N-3 effect involves more effective task shielding, which would be reflected in reduced congruency effects in trials following ABA, relative to trials following CBA; congruency effects did not differ between these conditions. Taken together, we can rule out two potential explanations of the N-3 effect: Neither is this effect due to enhanced task preparation, nor to more effective task shielding.

  19. Do walking strategies to increase physical activity reduce reported sitting in workplaces: a randomized control trial

    Directory of Open Access Journals (Sweden)

    Burton Nicola W

    2009-07-01

    Full Text Available Abstract Background Interventions designed to increase workplace physical activity may not automatically reduce high volumes of sitting, a behaviour independently linked to chronic diseases such as obesity and type II diabetes. This study compared the impact two different walking strategies had on step counts and reported sitting times. Methods Participants were white-collar university employees (n = 179; age 41.3 ± 10.1 years; 141 women, who volunteered and undertook a standardised ten-week intervention at three sites. Pre-intervention step counts (Yamax SW-200 and self-reported sitting times were measured over five consecutive workdays. Using pre-intervention step counts, employees at each site were randomly allocated to a control group (n = 60; maintain normal behaviour, a route-based walking group (n = 60; at least 10 minutes sustained walking each workday or an incidental walking group (n = 59; walking in workday tasks. Workday step counts and reported sitting times were re-assessed at the beginning, mid- and endpoint of intervention and group mean± SD steps/day and reported sitting times for pre-intervention and intervention measurement points compared using a mixed factorial ANOVA; paired sample-t-tests were used for follow-up, simple effect analyses. Results A significant interactive effect (F = 3.5; p t = 3.9, p t = 2.5, p Conclusion Compared to controls, both route and incidental walking increased physical activity in white-collar employees. Our data suggests that workplace walking, particularly through incidental movement, also has the potential to decrease employee sitting times, but there is a need for on-going research using concurrent and objective measures of sitting, standing and walking.

  20. Result of randomized control trial to increase breast health awareness among young females in Malaysia

    Directory of Open Access Journals (Sweden)

    Mehrnoosh Akhtari-Zavare

    2016-08-01

    Full Text Available Abstract Background Breast cancer is the most common cancer and the second principal cause of cancer deaths in women worldwide as well as in Malaysia. Breast self-examination (BSE has a role in raising breast cancer awareness among women and educational programs play an important role in breast cancer preventive behavior. The aim of this study is to develop, implement and evaluate the effectiveness of Breast Health Awareness program based on health belief model on knowledge of breast cancer and breast-selfexamination and BSE practice among female students in Malaysia. Methods A single-blind randomized controlled trial was carried out among 370 female undergraduate students from January 2011 to April 2012 in two selected public universities in Malaysia. Participants were randomized to either the intervention group or the control group. The educational program was delivered to the intervention group. The outcome measures were assessed at baseline, 6, and 12 months after implementing the health educational program. Chi-square, independent samples t-test and two-way repeated measures ANOVA (GLM were conducted in the course of the data analyses. Results Mean scores of knowledge on breast cancer (p<0.003, knowledge on breast self examination (p<0.001, benefits of BSE (p<0.00, barrier of BSE (0.01 and confidence of BSE practice (p<0.00 in the intervention group had significant differences in comparison with those of the control group 6 and 12 months after the intervention. Also, among those who never practiced BSE at baseline, frequency of BSE practice increased 6 and 12 months after the intervention (p<0.05. Conclusion The Breast Health Awareness program based on health the belief model had a positive effect on knowledge of breast cancer and breast self-examination and practice of BSE among females in Malaysia. Trial registration The ANZCTR clinical trial registry ( ACTRN12616000831482 , retrospectively registered on Jun 23, 2016 in ANZCTR.org.au.

  1. Increased reward in ankle robotics training enhances motor control and cortical efficiency in stroke.

    Science.gov (United States)

    Goodman, Ronald N; Rietschel, Jeremy C; Roy, Anindo; Jung, Brian C; Diaz, Jason; Macko, Richard F; Forrester, Larry W

    2014-01-01

    Robotics is rapidly emerging as a viable approach to enhance motor recovery after disabling stroke. Current principles of cognitive motor learning recognize a positive relationship between reward and motor learning. Yet no prior studies have established explicitly whether reward improves the rate or efficacy of robotics-assisted rehabilitation or produces neurophysiologic adaptations associated with motor learning. We conducted a 3 wk, 9-session clinical pilot with 10 people with chronic hemiparetic stroke, randomly assigned to train with an impedance-controlled ankle robot (anklebot) under either high reward (HR) or low reward conditions. The 1 h training sessions entailed playing a seated video game by moving the paretic ankle to hit moving onscreen targets with the anklebot only providing assistance as needed. Assessments included paretic ankle motor control, learning curves, electroencephalograpy (EEG) coherence and spectral power during unassisted trials, and gait function. While both groups exhibited changes in EEG, the HR group had faster learning curves (p = 0.05), smoother movements (p increase in nonparetic step length (p = 0.05) in the HR group only. These results suggest that combining explicit rewards with novel anklebot training may accelerate motor learning for restoring mobility.

  2. Target-nontarget similarity decreases search efficiency and increases stimulus-driven control in visual search.

    Science.gov (United States)

    Barras, Caroline; Kerzel, Dirk

    2017-10-01

    Some points of criticism against the idea that attentional selection is controlled by bottom-up processing were dispelled by the attentional window account. The attentional window account claims that saliency computations during visual search are only performed for stimuli inside the attentional window. Therefore, a small attentional window may avoid attentional capture by salient distractors because it is likely that the salient distractor is located outside the window. In contrast, a large attentional window increases the chances of attentional capture by a salient distractor. Large and small attentional windows have been associated with efficient (parallel) and inefficient (serial) search, respectively. We compared the effect of a salient color singleton on visual search for a shape singleton during efficient and inefficient search. To vary search efficiency, the nontarget shapes were either similar or dissimilar with respect to the shape singleton. We found that interference from the color singleton was larger with inefficient than efficient search, which contradicts the attentional window account. While inconsistent with the attentional window account, our results are predicted by computational models of visual search. Because of target-nontarget similarity, the target was less salient with inefficient than efficient search. Consequently, the relative saliency of the color distractor was higher with inefficient than with efficient search. Accordingly, stronger attentional capture resulted. Overall, the present results show that bottom-up control by stimulus saliency is stronger when search is difficult, which is inconsistent with the attentional window account.

  3. Potentially functional polymorphism in IL-23 receptor and risk of acute myeloid leukemia in a Chinese population.

    Directory of Open Access Journals (Sweden)

    Xifeng Qian

    Full Text Available The interleukin-23 (IL-23 and its receptor (IL-23R mediate the direct antitumor activities in human hematologic malignancies including pediatric acute leukemia. Two potentially functional genetic variants (IL-23R rs1884444 T>G and rs6682925 T>C have been found to contribute to solid cancer susceptibility. In this study, we conducted a case-control study including 545 acute myeloid leukemia (AML patients and 1,146 cancer-free controls in a Chinese population to assess the association between these two SNPs and the risk of AML. We found that IL-23R rs1884444 TG/GG and rs6682925 TC/CC variant genotypes were associated with significantly increased risk of AML [rs1884444: adjusted odds ratio (OR = 1.28, 95% confidence interval (CI = 1.01-1.62; rs6682925: adjusted OR = 1.30, 95%CI = 1.01-1.67], compared to their corresponding wild-type homozygotes, respectively. These findings indicated that genetic variants in IL-23R may contribute to AML risk in our Chinese population.

  4. Splenectomy suppresses growth and metastasis of hepatocellular carcinoma through decreasing myeloid-derived suppressor cells in vivo.

    Science.gov (United States)

    Long, Xin; Wang, Jian; Zhao, Jian-Ping; Liang, Hui-Fang; Zhu, Peng; Cheng, Qi; Chen, Qian; Wu, Yan-Hui; Zhang, Zhan-Guo; Zhang, Bi-Xiang; Chen, Xiao-Ping

    2016-10-01

    The function of the spleen in tumor development has been investigated for years. The relationship of the spleen with hepatocellular carcinoma (HCC), a huge health burden worldwide, however, remains unknown. The present study aimed to examine the effect of splenectomy on the development of HCC and the possible mechanism. Mouse hepatic carcinoma lines H22 and Hepa1-6 as well as BALB/c and C57 mice were used to establish orthotopic and metastatic mouse models of liver cancer. Mice were divided into four groups, including control group, splenectomy control group (S group), tumor group (T group) and tumor plus splenectomy group (T+S group). Tumor growth, metastases and overall survival were assessed at determined time points. Meanwhile, myeloid-derived suppressor cells (MDSCs) were isolated from the peripheral blood (PB), the spleen and liver tumors, and then measured by flow cytometery. It was found that liver cancer led to splenomegaly, and increased the percentage of MDSCs in the PB and spleen in the mouse models. Splenectomy inhibited the growth and progression of liver cancer and prolonged the overall survival time of orthotopic and metastatic models, which was accompanied by decreased proportion of MDSCs in the PB and tumors of liver cancer-bearing mouse. It was suggested that splenectomy could be considered an adjuvant therapy to treat liver cancer.

  5. Acquired hemoglobin H disease in a patient with aplastic anemia evolving into acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Maria Stella Figueiredo

    Full Text Available CONTEXT: The prognosis of severe aplastic anemia has improved since the introduction of bone marrow transplantation and treatment with antithymocyte globulin. In contrast to the success of these protocols, studies with long term follow-up have shown the occurrence of clonal diseases such as paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome and acute leukemia in aplastic anemia. CASE REPORT: We report the first case of a Brazilian patient with aplastic anemia who developed myelodysplastic syndrome and acute myeloid leukemia showing acquired hemoglobin H and increased fetal hemoglobin.

  6. Radiation response of mouse lymphoid and myeloid cell lines. Pt. 1

    International Nuclear Information System (INIS)

    Radford, I.R.

    1994-01-01

    The sensitivity of 10 mouse lymphoid or myeloid cell lines to γ-ray- and DNA-associated 125 I-decay-induced clonogenic cell killing have been compared with their rate of loss of viability (membrane integrity) and with their putative cell type of origin. The increased sensitivity of haematopoietic cell lines to killing by DNA dsb may be related to their mode of death (apoptosis versus necrosis). Mode of cell death may thus be an important factor in determining the 'inherent radiosensitivity' of normal cells/tissues. Haematopoietic cell lines that undergo rapid interphase apoptotic death showed extreme sensitivity to DNA dsb. (author)

  7. Investigating power control in autonomous power systems with increasing wind power penetration

    Energy Technology Data Exchange (ETDEWEB)

    Margaris, Ioannis D. [National Technical Univ. of Athens (Greece). Electric Energy Systems Lab.; Hansen, Anca D.; Sorensen, Poul [Risoe National Laboratory, Roskilde (Denmark). Wind Energy Dept.; Hatziargyriou, Nikos D. [National Technical Univ. of Athens (Greece). Electric Energy Systems Lab.; Public Power Corporation S.A., Athens (Greece)

    2009-07-01

    Increasing levels of wind penetration in autonomous power systems has set intensively high standards with respect to wind turbine technology during the last years. Special features of non-interconnected power systems make security issues rather critical, as the operation of large wind farms like conventional power plants is becoming a necessity. This paper includes the study case of Rhodos island, in Greece, where rapidly increasing wind penetration has started to impose serious security issues for the immediate future. The scenarios studied here correspond to reference year of study 2012 and include wind farms with three different wind turbine technologies - namely Doubly Fed Induction Generator (DFIG), Permanent Magnet Synchronous Generator (PMSG) and Active Stall Induction Generator (ASIG) based wind turbines. Aggregated models of the wind farms are being used and results for different load cases are being analyzed and discussed. The ability of wind farms to assist in some of the power system control services traditionally carried out by conventional synchronous generation is being investigated and discussed. The power grid of the island, including speed governors and automatic voltage regulators, is simulated in the dedicated power system simulation program Power Factory from DIgSILENT. (orig.)

  8. Increase of Efficiency of Enterprise Financial Control through Application of the Integration Process

    Directory of Open Access Journals (Sweden)

    Hulay Ivanna O.

    2014-02-01

    Full Text Available The article analyses the modern state of an enterprise as of a socio-economic system, which consists of interconnected elements. The article states that each of these elements could be an individual structural subdivision of an enterprise. Establishment and maintenance of close links between the elements ensures increase of controllability of an enterprise and, at the same time, increase of economic indicators of enterprise activity. The article justifies urgency of integration, which should be realised not only at the level of an enterprise, but also at the level of each structural subdivision. It specifies selection of methods and approaches to the process of integration and shows that it is different for each enterprise and depends on goals and tasks, which have to be achieved in the result of realisation of each individual project. The article offers to use the process of integration at an enterprise, the goal of which is achievement of the system effect through unification of financial, material, information and human capital of an enterprise.

  9. The diversity of the pollen tube pathway in plants: towards an increasing control by the sporophyte

    Directory of Open Access Journals (Sweden)

    Jorge eLora

    2016-02-01

    Full Text Available Plants, unlike animals, alternate multicellular diploid and haploid generations in their life cycle. While this is widespread all along the plant kingdom, the size and autonomy of the diploid sporophyte and the haploid gametophyte generations vary along evolution. Vascular plants show an evolutionary trend towards a reduction of the gametophyte, reflected both in size and lifespan, together with an increasing dependence from the sporophyte. This has resulted in an overlooking of the importance of the gametophytic phase in the evolution of higher plants. This reliance on the sporophyte is most notorious along the pollen tube journey, where the male gametophytes have to travel a long way inside the sporophyte to reach the female gametophyte. Along evolution, there is a change in the scenery of the pollen tube pathway that favors pollen competition and selection. This trend, towards apparently making complicated what could be simple, appears to be related to an increasing control of the sporophyte over the gametophyte with implications for understanding plant evolution.

  10. Increasing arousal enhances inhibitory control in calm but not excitable dogs

    Science.gov (United States)

    Bray, Emily E.; MacLean, Evan L.; Hare, Brian A.

    2015-01-01

    The emotional-reactivity hypothesis proposes that problem-solving abilities can be constrained by temperament, within and across species. One way to test this hypothesis is with the predictions of the Yerkes-Dodson law. The law posits that arousal level, a component of temperament, affects problem solving in an inverted U-shaped relationship: optimal performance is reached at intermediate levels of arousal and impeded by high and low levels. Thus, a powerful test of the emotional-reactivity hypothesis is to compare cognitive performance in dog populations that have been bred and trained based in part on their arousal levels. We therefore compared a group of pet dogs to a group of assistance dogs bred and trained for low arousal (N = 106) on a task of inhibitory control involving a detour response. Consistent with the Yerkes-Dodson law, assistance dogs, which began the test with lower levels of baseline arousal, showed improvements when arousal was artificially increased. In contrast, pet dogs, which began the test with higher levels of baseline arousal, were negatively affected when their arousal was increased. Furthermore, the dogs’ baseline levels of arousal, as measured in their rate of tail wagging, differed by population in the expected directions. Low-arousal assistance dogs showed the most inhibition in a detour task when humans eagerly encouraged them while more highly aroused pet dogs performed worst on the same task with strong encouragement. Our findings support the hypothesis that selection on temperament can have important implications for cognitive performance. PMID:26169659

  11. Hypoxia-induced angiogenesis is increased by the controlled release of deferoxiamine from gelatin hydrogels.

    Science.gov (United States)

    Saito, Takashi; Tabata, Yasuhiko

    2014-08-01

    The objective of this study is to design biodegradable hydrogels for the controlled release of deferoxiamine (DFO) and evaluate their biological activity. When the DFO was added to human umbilical vein endothelial cells cultured in 5.0% O2, the level of hypoxia-inducible factor-1α and vascular endothelial growth factor significantly increased compared with that without DFO. The expression of angiogenesis-related genes was accordingly increased by the DFO addition. An aqueous solution of mixed gelatin and DFO was freeze-dried, and dehydrothermally treated at 140°C for 24h to prepare a gelatin hydrogel incorporating DFO. In the release test with phosphate-buffered saline solution (PBS) at 37°C, an initial DFO release of 60% was observed, followed by no release. When placed in PBS containing collagenase, the hydrogel was enzymatically degraded with time, and consequently released DFO in a degradation-dependent manner. After the hydrogel incorporating DFO was injected intramuscularly into a mouse model of hind limb ischemia, the number of new blood vessels formed was significantly higher than that with free DFO and DFO-free hydrogel. It is concluded that the DFO-containing hydrogel shows promising for inducing angiogenesis locally. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  12. Increasing arousal enhances inhibitory control in calm but not excitable dogs.

    Science.gov (United States)

    Bray, Emily E; MacLean, Evan L; Hare, Brian A

    2015-11-01

    The emotional-reactivity hypothesis proposes that problem-solving abilities can be constrained by temperament, within and across species. One way to test this hypothesis is with the predictions of the Yerkes-Dodson law. The law posits that arousal level, a component of temperament, affects problem solving in an inverted U-shaped relationship: Optimal performance is reached at intermediate levels of arousal and impeded by high and low levels. Thus, a powerful test of the emotional-reactivity hypothesis is to compare cognitive performance in dog populations that have been bred and trained based in part on their arousal levels. We therefore compared a group of pet dogs to a group of assistance dogs bred and trained for low arousal (N = 106) on a task of inhibitory control involving a detour response. Consistent with the Yerkes-Dodson law, assistance dogs, which began the test with lower levels of baseline arousal, showed improvements when arousal was artificially increased. In contrast, pet dogs, which began the test with higher levels of baseline arousal, were negatively affected when their arousal was increased. Furthermore, the dogs' baseline levels of arousal, as measured in their rate of tail wagging, differed by population in the expected directions. Low-arousal assistance dogs showed the most inhibition in a detour task when humans eagerly encouraged them, while more highly aroused pet dogs performed worst on the same task with strong encouragement. Our findings support the hypothesis that selection on temperament can have important implications for cognitive performance.

  13. Myeloid Sarcoma after Allogenic Stem Cell Transplantation for Acute Myeloid Leukemia: Successful Consolidation Treatment Approaches in Two Patients

    Directory of Open Access Journals (Sweden)

    Silje Johansen

    2018-01-01

    Full Text Available Myeloid sarcoma is an extramedullary (EM manifestation (i.e., manifestation outside the bone marrow of acute myeloid leukemia (AML; it is assumed to be relatively uncommon and can be the only manifestation of leukemia relapse after allogenic stem cell transplantation (allo-SCT. An EM sarcoma can manifest in any part of the body, although preferentially manifesting in immunological sanctuary sites as a single or multiple tumors. The development of myeloid sarcoma after allo-SCT is associated with certain cytogenetic abnormalities, developing of graft versus host disease (GVHD, and treatment with donor lymphocytes infusion (DLI. It is believed that posttransplant myeloid sarcomas develop because the EM sites evade immune surveillance. We present two patients with EM myeloid sarcoma in the breast and epipharynx, respectively, as the only manifestation of leukemia relapse. Both patients were treated with a combination of local and systemic therapy, with successfully longtime disease-free survival. Based on these two case reports, we give an updated review of the literature and discuss the pathogenesis, diagnosis, and treatment of EM sarcoma as the only manifestation of AML relapse after allo-SCT. There are no standard guidelines for the treatment of myeloid sarcomas in allotransplant recipients. In our opinion, the treatment of these patients needs to be individualized and should include local treatment (i.e., radiotherapy combined with systemic therapy (i.e., chemotherapy, immunotherapy, DLI, or retransplantation. The treatment has to consider both the need for sufficient antileukemic efficiency versus the risk of severe complications due to cumulative toxicity.

  14. Cost-effectiveness and quality-of-life assessment of GM-CSF as an adjunct to intensive remission induction chemotherapy in elderly patients with acute myeloid leukaemia

    NARCIS (Netherlands)

    Uyl-de Groot, CA; Lowenberg, B; Vellenga, E; Suciu, S; Willemze, R; Rutten, FFH

    We conducted a prospective, randomized, multicentre clinical trial comparing the effects and costs of GM-CSF as an adjunct to intensive chemotherapy in elderly patients with acute myeloid leukaemia (AML). The patients were randomized to either daunomycin-cytosine arabinoside (control arm: rr = 161)

  15. Effectiveness of a smartphone app in increasing physical activity amongst male adults: a randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Tim Harries

    2016-09-01

    Full Text Available Abstract Background Smartphones are ideal for promoting physical activity in those with little intrinsic motivation for exercise. This study tested three hypotheses: H1 – receipt of social feedback generates higher step-counts than receipt of no feedback; H2 – receipt of social feedback generates higher step-counts than only receiving feedback on one’s own walking; H3 – receipt of feedback on one’s own walking generates higher step-counts than no feedback (H3. Methods A parallel group randomised controlled trial measured the impact of feedback on steps-counts. Healthy male participants (n = 165 aged 18–40 were given phones pre-installed with an app that recorded steps continuously, without the need for user activation. Participants carried these with them as their main phones for a two-week run-in and six-week trial. Randomisation was to three groups: no feedback (control; personal feedback on step-counts; group feedback comparing step-counts against those taken by others in their group. The primary outcome measure, steps per day, was assessed using longitudinal multilevel regression analysis. Control variables included attitude to physical activity and perceived barriers to physical activity. Results Fifty-five participants were allocated to each group; 152 completed the study and were included in the analysis: n = 49, no feedback; n = 53, individual feedback; n = 50, individual and social feedback. The study provided support for H1 and H3 but not H2. Receipt of either form of feedback explained 7.7 % of between-subject variability in step-count (F = 6.626, p < 0.0005. Compared to the control, the expected step-count for the individual feedback group was 60 % higher (effect on log step-count = 0.474, 95 % CI = 0.166–0.782 and that for the social feedback group, 69 % higher (effect on log step-count = 0.526, 95 % CI = 0.212–0.840. The difference between the two feedback groups

  16. Reduction of myeloid-derived suppressor cells and lymphoma growth by a natural triterpenoid.

    Science.gov (United States)

    Radwan, Faisal F Y; Hossain, Azim; God, Jason M; Leaphart, Nathan; Elvington, Michelle; Nagarkatti, Mitzi; Tomlinson, Stephen; Haque, Azizul

    2015-01-01

    Lymphoma is a potentially life threatening disease. The goal of this study was to investigate the therapeutic potential of a natural triterpenoid, Ganoderic acid A (GA-A) in controlling lymphoma growth both in vitro and in vivo. Here, we show that GA-A treatment induces caspase-dependent apoptotic cell death characterized by a dose-dependent increase in active caspases 9 and 3, up-regulation of pro-apoptotic BIM and BAX proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA-A's anti-growth activity, we show that lower doses of GA-A enhance HLA class II-mediated antigen (Ag) presentation and CD4+ T cell recognition of lymphoma cells in vitro. The therapeutic relevance of GA-A treatment was also tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA-A-treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked down-regulation of STAT3 phosphorylation, reduction myeloid-derived suppressor cells (MDSCs), and enhancement of cytotoxic CD8+ T cells in the host. Thus, GA-A not only selectively induces apoptosis in lymphoma cells, but also enhances cell-mediated immune responses by attenuating MDSCs, and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA-A is a candidate for future drug design for the treatment of lymphoma. © 2014 Wiley Periodicals, Inc.

  17. Increasing the response rate of text messaging data collection: a delayed randomized controlled trial

    Science.gov (United States)

    Li, Ye; Wang, Wei; Wu, Qiong; van Velthoven, Michelle Helena; Chen, Li; Du, Xiaozhen; Zhang, Yanfeng; Rudan, Igor; Car, Josip

    2015-01-01

    Objective To test the effectiveness of multiple interventions on increasing the response rate of text messaging for longitudinal data collection. Methods Our cohort included 283 caregivers of children aged 6–12 months who were participating in an anemia program in rural China. Using text messages to collect data on anemia medication adherence, we conducted a delayed randomized controlled trial to test multiple interventions (an additional four reminders; a ¥5.0 (US$0.79) credit reward for replying; and a feedback text message). After a 6-week pilot study with week 7 as the baseline measurement, we randomly allocated all participants into two groups: group 1 (n = 142) and group 2 (n = 141). During weeks 8–11, we introduced the interventions to group 1, and in weeks 12–15 the intervention was introduced to both groups. We compared the response rates between groups and explored factors affecting the response rate. Results During weeks 8–11, the response rates in group 1 increased and were significantly higher than in group 2 (p0.05) and slightly decreased in group 1. Younger participants or participants who had children with lower hemoglobin concentration were more likely to reply (p = 0.02). Sending four reminders on the second day contributed to only 286 (11.7%) extra text messages. Discussion Our study showed that multiple interventions were effective in increasing response rate of text messaging data collection in rural China. Conclusions Larger multi-site studies are needed to find the most effective way of using these interventions to allow usage of text messaging data collection for health research. PMID:25332355

  18. Increasing intention to cook from basic ingredients: A randomised controlled study.

    Science.gov (United States)

    Lavelle, Fiona; Hollywood, Lynsey; Caraher, Martin; McGowan, Laura; Spence, Michelle; Surgenor, Dawn; McCloat, Amanda; Mooney, Elaine; Raats, Monique; Dean, Moira

    2017-09-01

    The promotion of home cooking is a strategy used to improve diet quality and health. However, modern home cooking typically includes the use of processed food which can lead to negative outcomes including weight gain. In addition, interventions to improve cooking skills do not always explain how theory informed their design and implementation. The Behaviour Change Technique (BCT) taxonomy successfully employed in other areas has identified essential elements for interventions. This study investigated the effectiveness of different instructional modes for learning to cook a meal, designed using an accumulating number of BCTs, on participant's perceived difficulty, enjoyment, confidence and intention to cook from basic ingredients. 141 mothers aged between 20 and 39 years from the island of Ireland were randomised to one of four conditions based on BCTs (1) recipe card only [control condition]; (2) recipe card plus video modelling; (3) recipe card plus video prompting; (4) recipe card plus video elements. Participants rated their enjoyment, perceived difficulty, confidence and intention to cook again pre, mid and post experiment. Repeated one-way factorial ANOVAs, correlations and a hierarchical regression model were conducted. Despite no significant differences between the different conditions, there was a significant increase in enjoyment (P cook from basics again (P cook from basics pre-experiment, and confidence and enjoyment (both pre and post experiment) significantly contributed to the final regression model explaining 42% of the variance in intention to cook from basics again. Cooking interventions should focus on practical cooking and increasing participants' enjoyment and confidence during cooking to increase intention to cook from basic ingredients at home. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).

    Science.gov (United States)

    Xu, Zheng; Li, Weixin; Han, Jibo; Zou, Chunpeng; Huang, Weijian; Yu, Weihui; Shan, Xiaoou; Lum, Hazel; Li, Xiaokun; Liang, Guang

    2017-03-21

    Growing evidence indicates that angiotensin II (Ang II), a potent biologically active product of RAS, is a key regulator of renal inflammation and fibrosis. In this study, we tested the hypothesis that Ang II induces renal inflammatory injury and fibrosis through interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system. Results indicated that in MD2 -/- mice, the Ang II-induced renal fibrosis, inflammation and kidney dysfunction were significantly reduced compared to control Ang II-infused wild-type mice. Similarly, in the presence of small molecule MD2 specific inhibitor L6H21 or siRNA-MD2, the Ang II-induced increases of pro-fibrotic and pro-inflammatory molecules were prevented in tubular NRK-52E cells. MD2 blockade also inhibited activation of NF-κB and ERK. Moreover, MD2 blockade prevented the Ang II-stimulated formation of the MD2/TLR4/MyD88 signaling complex, as well as the increased surface binding of Ang II in NRK-52E cells. In addition, Ang II directly bound recombinant MD2 protein, rather than TLR4 protein. We conclude that MD2 is a significant contributor in the Ang II-induced kidney inflammatory injury in chronic renal diseases. Furthermore, MD2 inhibition could be a new and important therapeutic strategy for preventing progression of chronic renal diseases.

  20. Voltage-Sensitive Load Controllers for Voltage Regulation and Increased Load Factor in Distribution Systems

    DEFF Research Database (Denmark)

    Douglass, Philip James; Garcia-Valle, Rodrigo; Østergaard, Jacob

    2014-01-01

    This paper presents a novel controller design for controlling appliances based on local measurements of voltage. The controller finds the normalized voltage deviation accounting for the sensitivity of voltage measurements to appliance state. The controller produces a signal indicating desired pow...

  1. Selecting the Best Frontline Treatment in Chronic Myeloid Leukemia

    Science.gov (United States)

    Yilmaz, Musa; Abaza, Yasmin; Jabbour, Elias

    2017-01-01

    With the discovery of Philadelphia chromosome, understanding of chronic myeloid leukemia (CML) pathobiology has tremendously increased. Development of tyrosine kinase inhibitors (TKI) targeting the BCR/ABL1 oncoprotein has changed the landscape of the disease. Today, the expected survival of CML patients, if properly managed, is likely to be similar to the general population. Imatinib is the first approved TKI in CML treatment, and for several years, it was the only option in the frontline setting. Four years ago, second generation TKIs (nilotinib and dasatinib) were approved as alternative frontline options. Now, clinicians are faced the challenge of making decision for which TKI to chose upfront. Second generation TKIs have been demonstrated to induce deeper and faster responses compared to imatinib, however, none of 3 TKIs have been shown to have a clear survival advantage, they all are reasonable options. In contrast, when considering therapy in individual patients, the case may be stronger for a specific TKI. Co-morbidities of the patient and side effect profile of the TKI of interest should be an important consideration in decision making. At present, the cost nilotinib or dasatinib is not remarkably different from imatinib. However, patent for imatinib is expected to expire soon, and it will be available as a generic. Clinicians, then, need to weigh the advantages some patients gain with nilotinib or dasatinib in the frontline setting against the difference in cost. Whatever TKI is chosen as frontline, intolerance, non-compliance or treatment failure should be recognized early as a prompt intervention increases the chance of achieving best possible response. PMID:25921387

  2. Diagnostic confusion resulting from CD56 expression by cutaneous myeloid sarcoma

    Directory of Open Access Journals (Sweden)

    Sheeja T. Pullarkat

    2009-12-01

    Full Text Available Myeloid sarcomas are tumor masses composed of aggregates of malignant myeloid precursors in extramedullary sites including the skin. We report a case of myeloid sarcoma in a patient who presented with an ear lobe mass and facial nerve paralysis. Expression of CD56 by the malignant cells led to an initial misdiagnosis as Merkel cell tumor. Comprehensive pathological evaluation confirmed the diagnosis of myeloid sarcoma with aberrant expression of CD56 and carrying the translocation t(8;21 (q22;q22. Aberrant antigen expression by cutaneous myeloid sarcomas can cause diagnostic confusion with other cutaneous neoplasms. This is especially relevant when myeloid sarcoma is the sole manifestation of acute myeloid leukemia.

  3. Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells.

    Directory of Open Access Journals (Sweden)

    Bernhard F Gibbs

    Full Text Available Stem cell factor (SCF is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1 in hematopoietic cells--a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation--an important stage of the myeloid leukaemia cell life cycle.

  4. "MY PKU": increasing self-management in patients with phenylketonuria. A randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Jonkers Cora F

    2011-06-01

    Full Text Available Abstract Background Phenylketonuria (PKU is an autosomal recessive disorder of phenylalanine metabolism. The inability to convert phenylalanine (Phe into tyrosine causes Phe to accumulate in the body. Adherence to a protein restricted diet, resulting in reduced Phe levels, is essential to prevent cognitive decline. Frequent evaluation of plasma Phe levels and, if necessary, adjustment of the diet are the mainstay of treatment. We aimed to assess whether increased self-management of PKU patients and/or their parents is feasible and safe, by providing direct online access to blood Phe values without immediate professional guidance. Methods Thirty-eight patients aged ≥ 1 year participated in a 10 month randomized controlled trial. Patients were randomized into a study group (1 or a control group (2. Group 2 continued the usual procedure: a phone call or e-mail by a dietician in case of a deviant Phe value. Group 1 was given a personal "My PKU" web page with a graph of their recent and previous Phe values, online general information about the dietary treatment and the Dutch PKU follow-up guidelines, and a message-box to contact their dietician if necessary. Phe values were provided on "My PKU" without advice. Outcome measures were: differences in mean Phe value, percentage of values above the recommended range and Phe sample frequency, between a 10-month pre-study period and the study period in each group, and between the groups in both periods. Furthermore we assessed satisfaction of patients and/or parents with the 'My PKU' procedure of online availability. Results There were no significant differences in mean Phe value, percentage of values above recommended range or in frequency of blood spot sampling for Phe determination between the pre-study period and the study period in each group, nor between the 2 groups during the periods. All patients and/or parents expressed a high level of satisfaction with the new way of disease management

  5. Increased alertness, better than posture prioritization, explains dual-task performance in prosthesis users and controls under increasing postural and cognitive challenge.

    Science.gov (United States)

    Howard, Charla L; Perry, Bonnie; Chow, John W; Wallace, Chris; Stokic, Dobrivoje S

    2017-11-01

    Sensorimotor impairments after limb amputation impose a threat to stability. Commonly described strategies for maintaining stability are the posture first strategy (prioritization of balance) and posture second strategy (prioritization of concurrent tasks). The existence of these strategies was examined in 13 below-knee prosthesis users and 15 controls during dual-task standing under increasing postural and cognitive challenge by evaluating path length, 95% sway area, and anterior-posterior and medial-lateral amplitudes of the center of pressure. The subjects stood on two force platforms under usual (hard surface/eyes open) and difficult (soft surface/eyes closed) conditions, first alone and while performing a cognitive task without and then with instruction on cognitive prioritization. During standing alone, sway was not significantly different between groups. After adding the cognitive task without prioritization instruction, prosthesis users increased sway more under the dual-task than single-task standing (p ≤ 0.028) during both usual and difficult conditions, favoring the posture second strategy. Controls, however, reduced dual-task sway under a greater postural challenge (p ≤ 0.017), suggesting the posture first strategy. With prioritization of the cognitive task, sway was unchanged or reduced in prosthesis users, suggesting departure from the posture second strategy, whereas controls maintained the posture first strategy. Individual analysis of dual tasking revealed that greater postural demand in controls and greater cognitive challenge in prosthesis users led to both reduced sway and improved cognitive performance, suggesting cognitive-motor facilitation. Thus, activation of additional resources through increased alertness, rather than posture prioritization, may explain dual-task performance in both prosthesis users and controls under increasing postural and cognitive challenge.

  6. Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells

    International Nuclear Information System (INIS)

    Eshel, Rinat; Ben-Zaken, Olga; Vainas, Oded; Nadir, Yona; Minucci, Saverio; Polliack, Aaron; Naparstek, Ella; Vlodavsky, Israel; Katz, Ben-Zion

    2005-01-01

    Heparanase is a heparan sulfate-degrading endoglycosidase expressed by mature monocytes and myeloid cells, but not by immature hematopoietic progenitors. Heparanase gene expression is upregulated during differentiation of immature myeloid cells. PML-RARα and PLZF-RARα fusion gene products associated with acute promyelocytic leukemia abrogate myeloid differentiation and heparanase expression. AML-Eto, a translocation product associated with AML FAB M2, also downregulates heparanase gene expression. The common mechanism that underlines the activity of these three fusion gene products involves the recruitment of histone deacetylase complexes to specific locations within the DNA. We found that retinoic acid that dissociates PML-RARα from the DNA, and which is used to treat acute promyelocytic leukemia patients, restores heparanase expression to normal levels in an acute promyelocytic leukemia cell line. The retinoic acid effects were also observed in primary acute promyelocytic leukemia cells and in a retinoic acid-treated acute promyelocytic leukemia patient. Histone deacetylase inhibitor reverses the downregulation of heparanase expression induced by the AML-Eto fusion gene product in M2 type AML. In summary, we have characterized a link between leukomogenic factors and the downregulation of heparanase in myeloid leukemic cells

  7. Occupational exposure to solvents and acute myeloid leukemia

    DEFF Research Database (Denmark)

    Talibov, Madar; Lehtinen-Jacks, Susanna; Martinsen, Jan Ivar

    2014-01-01

    OBJECTIVE: The aim of the current study was to assess the relation between occupational exposure to solvents and the risk of acute myeloid leukemia (AML). METHODS: Altogether, this study comprises 15 332 incident cases of AML diagnosed in Finland, Norway, Sweden and Iceland from 1961-2005 and 76...

  8. Interferon alpha for treatment of chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Hjorth-Hansen, Henrik; Bjerrum, Ole Weis

    2011-01-01

    Treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-a) was introduced in the early 1980s. Several clinical trials showed a survival advantage for patients treated with IFN-a compared to conventional chemotherapy. Some patients achieved longstanding complete cytogenetic remissions...

  9. Cytokine Networks between Innate Lymphoid Cells and Myeloid Cells.

    Science.gov (United States)

    Mortha, Arthur; Burrows, Kyle

    2018-01-01

    Innate lymphoid cells (ILCs) are an essential component of the innate immune system in vertebrates. They are developmentally rooted in the lymphoid lineage and can diverge into at least three transcriptionally distinct lineages. ILCs seed both lymphoid and non-lymphoid tissues and are locally self-maintained in tissue-resident pools. Tissue-resident ILCs execute important effector functions making them key regulator in tissue homeostasis, repair, remodeling, microbial defense, and anti-tumor immunity. Similar to T lymphocytes, ILCs possess only few sensory elements for the recognition of non-self and thus depend on extrinsic cellular sensory elements residing within the tissue. Myeloid cells, including mononuclear phagocytes (MNPs), are key sentinels of the tissue and are able to translate environmental cues into an effector profile that instructs lymphocyte responses. The adaptation of myeloid cells to the tissue state thus influences the effector program of ILCs and serves as an example of how environmental signals are integrated into the function of ILCs via a tissue-resident immune cell cross talks. This review summarizes our current knowledge on the role of myeloid cells in regulating ILC functions and discusses how feedback communication between ILCs and myeloid cells contribute to stabilize immune homeostasis in order to maintain the healthy state of an organ.

  10. Therapy related Acute Myeloid Leukaemia 8 Years after Treatment ...

    African Journals Online (AJOL)

    Hodgkin's Disease (HD) is a curable malignancy even in Nigeria, our limitations in health care delivery notwithstanding. However, secondary malignancies especially Acute Myeloid Leukaemia (AML) may occur as late complications following alkylating cytotoxic drugs therapy, with or without radiotherapy. This is a case ...

  11. Myeloid sarcoma developing in pre-existing pyoderma gangrenosum

    DEFF Research Database (Denmark)

    Kristensen, Ida Bruun; Møller, Hanne; Kjaerskov, Mette Wanscher

    2009-01-01

    We report here a case of pyoderma gangrenosum in a patient with myelodysplastic syndrome developing into myeloid sarcoma as a sign of transformation to acute leukaemia. The patient was treated successfully with intensive chemotherapy and achieved complete remission, and her otherwise expanding...

  12. Peripheral retinal nonperfusion associated with chronic myeloid leukemia.

    NARCIS (Netherlands)

    Nobacht, S.; Vandoninck, K.F.; Deutman, A.F.; Klevering, B.J.

    2003-01-01

    PURPOSE: To report a case of peripheral retinal nonperfusion and chronic myeloid leukemia in a 23-year-old woman. DESIGN: Observational case report. METHODS: A complete ophthalmic and systemic evaluation was performed. RESULTS: Ophthalmic examination revealed peripheral retinal nonperfusion with

  13. Examining the Origins of Myeloid Leukemia | Center for Cancer Research

    Science.gov (United States)

    Acute myeloid leukemia or AML, a cancer of the white blood cells, is the most common type of rapidly-growing leukemia in adults. The over-production of white blood cells in the bone marrow inhibits the development of other necessary blood components including red blood cells, which carry oxygen throughout the body, and platelets, which are required for clot formation. The

  14. Association between MTHFR polymorphisms and acute myeloid leukemia risk: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Yu-Tao Qin

    Full Text Available Previous observational studies investigating the association between methylenetetrahydrofolate reductase (MTHFR polymorphisms and acute myeloid leukemia risk (AML have yielded inconsistent results. The aim of this study is to derive a more precise estimation of the association between MTHFR (C677T and A1298C polymorphisms and acute myeloid leukemia risk. PubMed and Embase databases were systematically searched to identify relevant studies from their inception to August 2013. Odds ratios (ORs with 95% confidence intervals (CIs were the metric of choice. Thirteen studies were selected for C677T polymorphism (1838 cases and 5318 controls and 9 studies (1335 patients and 4295 controls for A1298C polymorphism. Overall, pooled results showed that C677T polymorphism was not significant associated with AML risk(OR, 0.98-1.04; 95% CI, 0.86-0.92 to 1.09-1.25. Similar results were observed for the A1298C polymorphism and in subgroup analysis. All comparisons revealed no substantial heterogeneity nor did we detect evidence of publication bias. In summary, this meta-analysis provides evidence that MTHFR polymorphisms were not associated with AML risk. Further investigations are needed to offer better insight into the role of these polymorphisms in AML carcinogenesis.

  15. Home-based family intervention increases knowledge, communication and living donation rates: a randomized controlled trial.

    Science.gov (United States)

    Ismail, S Y; Luchtenburg, A E; Timman, R; Zuidema, W C; Boonstra, C; Weimar, W; Busschbach, J J V; Massey, E K

    2014-08-01

    Our aim was to develop and test an educational program to support well-informed decision making among patients and their social network regarding living donor kidney transplantation (LDKT). One hundred sixty-three patients who were unable to find a living donor were randomized to standard care or standard care plus home-based education. In the education condition, patients and members of their social network participated in home-based educational meetings and discussed renal replacement therapy options. Patients and invitees completed pre-post self-report questionnaires measuring knowledge, risk perception, communication, self-efficacy and subjective norm. LDKT activities were observed for 6 months postintervention. Patients in the experimental group showed significantly more improvements in knowledge (p communication (p = 0.012) compared with the control group. The invitees showed pre-post increases in knowledge (p decision making and promotes access to LDKT. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

  16. Potential To Increase Productivity And Sustainability In Argentinean Agriculture With Controlled Traffic Farming: A Short Discussion

    Directory of Open Access Journals (Sweden)

    Antille Diogenes L.

    2015-09-01

    Full Text Available Drivers for and potential barriers against adoption of controlled traffic farming (CTF systems in Argentina are reviewed. Traffic compaction is one of the main factors affecting crop productivity within Argentinean agriculture, and has significant although less quantified impacts on the whole-of-farm system. This suggests that the benefits of no-tillage (NT, which represents the dominant form of cropping in Argentina, are not fully realised. Conservative estimates indicate that crop yields could be improved by at least 15% if NT is used in conjunction with CTF. Cost-benefit analyses of available options for compaction management are required. Despite this, and based on reported evidence internationally, a shift toward increased uptake of CTF within Argentinean agriculture is likely to: (1 improve productivity and farm profitability, (2 enhance environmental performance, and (3 maintain competitiveness of the agricultural sector. Appropriate technical advice and support is a key requirement to drive adoption of CTF. Therefore, the adoption process will benefit from collaboration developed with well-established research and extension organisations in Australia and the United Kingdom, and active engagement of machinery manufacturers.

  17. Video-feedback intervention increases sensitive parenting in ethnic minority mothers: a randomized control trial.

    Science.gov (United States)

    Yagmur, Sengul; Mesman, Judi; Malda, Maike; Bakermans-Kranenburg, Marian J; Ekmekci, Hatice

    2014-01-01

    Using a randomized control trial design we tested the effectiveness of a culturally sensitive adaptation of the Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD) in a sample of 76 Turkish minority families in the Netherlands. The VIPP-SD was adapted based on a pilot with feedback of the target mothers, resulting in the VIPP-TM (VIPP-Turkish Minorities). The sample included families with 20-47-month-old children with high levels of externalizing problems. Maternal sensitivity, nonintrusiveness, and discipline strategies were observed during pretest and posttest home visits. The VIPP-TM was effective in increasing maternal sensitivity and nonintrusiveness, but not in enhancing discipline strategies. Applying newly learned sensitivity skills in discipline situations may take more time, especially in a cultural context that favors more authoritarian strategies. We conclude that the VIPP-SD program and its video-feedback approach can be successfully applied in immigrant families with a non-Western cultural background, with demonstrated effects on parenting sensitivity and nonintrusiveness.

  18. The Natural Antiangiogenic Compound AD0157 Induces Caspase-Dependent Apoptosis in Human Myeloid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Melissa García-Caballero

    2017-11-01

    Full Text Available Evasion of apoptosis is a hallmark of cancer especially relevant in the development and the appearance of leukemia drug resistance mechanisms. The development of new drugs that could trigger apoptosis in aggressive hematological malignancies, such as AML and CML, may be considered a promising antileukemic strategy. AD0157, a natural marine pyrrolidinedione, has already been described as a compound that inhibits angiogenesis by induction of apoptosis in endothelial cells. The crucial role played by defects in the apoptosis pathways in the pathogenesis, progression and response to conventional therapies of several forms of leukemia, moved us to analyze the effect of this compound on the growth and death of leukemia cells. In this work, human myeloid leukemia cells (HL60, U937 and KU812F were treated with AD0157 ranging from 1 to 10 μM and an experimental battery was applied to evaluate its apoptogenic potential. We report here that AD0157 was highly effective to inhibit cell growth by promotion of apoptosis in human myeloid leukemia cells, and provide evidence of its mechanisms of action. The apoptogenic activity of AD0157 on leukemia cells was verified by an increased chromatin condensation and DNA fragmentation, and confirmed by an augmentation in the apoptotic subG1 population, translocation of the membrane phosphatidylserine from the inner face of the plasma membrane to the cell surface and by cleavage of the apoptosis substrates PARP and lamin-A. In addition, AD0157 in the low micromolar range significantly enhanced the activities of the initiator caspases-8 and -9, and the effector caspases-3/-7 in a dose-dependent manner. Results presented here throw light on the apoptogenic mechanism of action of AD0157, mediated through caspase-dependent cascades, with an especially relevant role played by mitochondria. Altogether, these results suggest the therapeutic potential of this compound for the treatment of human myeloid leukemia.

  19. Canthin-6-one induces cell death, cell cycle arrest and differentiation in human myeloid leukemia cells.

    Science.gov (United States)

    Vieira Torquato, Heron F; Ribeiro-Filho, Antonio C; Buri, Marcus V; Araújo Júnior, Roberto T; Pimenta, Renata; de Oliveira, José Salvador R; Filho, Valdir C; Macho, Antonio; Paredes-Gamero, Edgar J; de Oliveira Martins, Domingos T

    2017-04-01

    Canthin-6-one is a natural product isolated from various plant genera and from fungi with potential antitumor activity. In the present study, we evaluate the antitumor effects of canthin-6-one in human myeloid leukemia lineages. Kasumi-1 lineage was used as a model for acute myeloid leukemia. Cells were treated with canthin-6-one and cell death, cell cycle and differentiation were evaluated in both total cells (Lin + ) and leukemia stem cell population (CD34 + CD38 - Lin -/low ). Among the human lineages tested, Kasumi-1 was the most sensitive to canthin-6-one. Canthin-6-one induced cell death with apoptotic (caspase activation, decrease of mitochondrial potential) and necrotic (lysosomal permeabilization, double labeling of annexin V/propidium iodide) characteristics. Moreover, canthin-6-one induced cell cycle arrest at G 0 /G 1 (7μM) and G 2 (45μM) evidenced by DNA content, BrdU incorporation and cyclin B1/histone 3 quantification. Canthin-6-one also promoted differentiation of Kasumi-1, evidenced by an increase in the expression of myeloid markers (CD11b and CD15) and the transcription factor PU.1. Furthermore, a reduction of the leukemic stem cell population and clonogenic capability of stem cells were observed. These results show that canthin-6-one can affect Kasumi-1 cells by promoting cell death, cell cycle arrest and cell differentiation depending on concentration used. Canthin-6-one presents an interesting cytotoxic activity against leukemic cells and represents a promising scaffold for the development of molecules for anti-leukemic applications, especially by its anti-leukemic stem cell activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Systemic agonistic anti-CD40 treatment of tumor bearing mice modulates hepatic myeloid suppressive cells and causes immune-mediated liver damage

    Science.gov (United States)

    Medina-Echeverz, José; Ma, Chi; Duffy, Austin; Eggert, Tobias; Hawk, Nga; Kleiner, David E.; Korangy, Firouzeh; Greten, Tim F.

    2015-01-01

    Immune stimulatory monoclonal antibodies are currently evaluated as anti tumor agents. Although overall toxicity appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in spleen and liver. Naïve and tumor-bearing mice were treated systemically with agonistic anti-CD40 antibody. Immune cell subsets in liver and spleen, serum transaminases and liver histologies were analyzed after antibody administration. Nox2−/−, Cd40−/− as well as bone marrow chimeric mice were used to study the mechanism by which agonistic anti-CD40 mediates its effects in vivo. Suppressor function of murine and human tumor-induced myeloid derived suppressive cells was studied upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras we demonstrated that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40-expressing hematopoietic cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80 and CD40 positive liver CD11b+Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced murine and human CD14+HLA-DRlow PBMC from cancer patients reduced their immune suppressor function. Collectively, agonistic CD40 antibody treatment activated tumor-induced, myeloid cells, caused myeloid dependent hepatotoxicity and ameliorated the suppressor function of murine and human MDSC. Collectively, our data suggests that CD40 may mature immunosuppressive myeloid cells and thereby cause liver damage in mice with an accumulation of tumor-induced hepatic MDSC. PMID:25637366

  1. Frontline treatment of acute myeloid leukemia in adults

    Science.gov (United States)

    Tamamyan, Gevorg; Kadia, Tapan; Ravandi, Farhad; Borthakur, Gautam; Cortes, Jorge; Jabbour, Elias; Daver, Naval; Ohanian, Maro; Kantarjian, Hagop; Konopleva, Marina

    2017-01-01

    Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients’ age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40–50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30–40% up to 80–90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the “7+3” regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the “7+3” regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future. PMID:28109402

  2. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis | Center for Cancer Research

    Science.gov (United States)

    We demonstrate a novel tumor-promoting role of myeloid immune suppressor Gr+CD11b+ cells, which are evident in cancer patients and tumor-bearing animals. These cells constitute approximately 5% of total cells in tumors. Tumors coinjected with Gr+CD11b+ cells exhibited increased vascular density, vascular maturation, and decreased necrosis. These immune cells produce high

  3. Distributed intelligence in a LAN architecture increases the flexibility in control systems for fusion experiments

    International Nuclear Information System (INIS)

    Tenten, W.; Fuss, L.; Hoge, W.

    1987-01-01

    The control system for the TEXTOR Neutral Beam Injectors is designed implementing approved concepts and techniques. A powerful super mini computer serves as a central node between the operators console and the experimental process. Devices form a console for suitable man machine interaction. The link to the process is mainly based on communication with a network of industry standard programmable controllers. A distinction is made between the functionally dedicated and in most cases locally distributed logic controllers, a central controller and the computerized console level. Introduction of such networks in control system for fusion experiments results in a number of advantages

  4. The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

    Directory of Open Access Journals (Sweden)

    Ilana Zalcberg Renault

    2011-12-01

    Full Text Available Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging.

  5. The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

    Science.gov (United States)

    Renault, Ilana Zalcberg; Scholl, Vanesa; Hassan, Rocio; Capelleti, Paola; de Lima, Marcos; Cortes, Jorge

    2011-01-01

    Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging. PMID:23049363

  6. Intensive chemotherapy for acute myeloid leukemia differentially affects circulating TC1, TH1, TH17 and TREG cells

    Directory of Open Access Journals (Sweden)

    Gjertsen Bjørn

    2010-07-01

    Full Text Available Abstract Background Several observations suggest that immunological events early after chemotherapy, possibly during the period of severe treatment-induced cytopenia, are important for antileukemic immune reactivity in acute myeloid leukemia (AML. We therefore investigated the frequencies of various T cell subsets (TC1, TH1, TH17 and CD25+ FoxP3+ TREG cells in AML patients with untreated disease and following intensive chemotherapy. Results Relative levels of circulating TC1 and TH1 cells were decreased in patients with severe chemotherapy-induced cytopenia, whereas TH17 levels did not differ from healthy controls. Increased levels of regulatory CD25+ FoxP3+ T cells were detected in AML patients with untreated disease, during chemotherapy-induced cytopenia and during regeneration after treatment. TH17 and TH1 levels were significantly higher in healthy males than females, but this gender difference was not detected during chemotherapy-induced cytopenia. Finally, exogenous IL17-A usually had no or only minor effects on proliferation of primary human AML cells. Conclusions We conclude that the effect of intensive AML chemotherapy differ between circulating T cell subsets, relative frequencies of TH17 cells are not affected by chemotherapy and this subset may affect AML cells indirectly through their immunoregulatory effects but probably not through direct effects of IL17-A.

  7. Mesenchymal stromal cells from patients with acute myeloid leukemia have altered capacity to expand differentiated hematopoietic progenitors.

    Science.gov (United States)

    Chandran, Priya; Le, Yevgeniya; Li, Yuhua; Sabloff, Mitchell; Mehic, Jelica; Rosu-Myles, Michael; Allan, David S

    2015-04-01

    The bone marrow microenvironment may be permissive to the emergence and progression of acute myeloid leukemia (AML). Studying interactions between the microenvironment and leukemia cells should provide new insight for therapeutic advances. Mesenchymal stromal cells (MSCs) are central to the maintenance of the hematopoietic niche. Here we compared the functions and gene expression patterns of MSCs derived from bone marrow aspirates of healthy donors and patients with AML. MSCs expanded from AML patients had heterogeneous morphology and displayed a wide range of proliferation capacity compared to MSCs from healthy controls. The ability of AML-MSCs to support the expansion of committed hematopoietic progenitors from umbilical cord blood-derived CD34+ cells may be impaired while the expression of genes associated with maintaining hematopoietic quiescence appeared to be increased in AML-MSCs compared to healthy donors. These results highlight important potential differences in the biologic profile of MSCs from AML patients compared to healthy donors that may contribute to the emergence or progression of leukemia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. A Rapid Culture Technique Produces Functional Dendritic-Like Cells from Human Acute Myeloid Leukemia Cell Lines

    Directory of Open Access Journals (Sweden)

    Jian Ning

    2011-01-01

    Full Text Available Most anti-cancer immunotherapeutic strategies involving dendritic cells (DC as vaccines rely upon the adoptive transfer of DC loaded with exogenous tumour-peptides. This study utilized human acute myeloid leukemia (AML cells as progenitors from which functional dendritic-like antigen presenting cells (DLC were generated, that constitutively express tumour antigens for recognition by CD8+ T cells. DLC were generated from AML cell lines KG-1 and MUTZ-3 using rapid culture techniques and appropriate cytokines. DLC were evaluated for their cell-surface phenotype, antigen uptake and ability to stimulate allogeneic responder cell proliferation, and production of IFN-γ; compared with DC derived from normal human PBMC donors. KG-1 and MUTZ-3 DLC increased expression of CD80, CD83, CD86, and HLA-DR, and MUTZ-3 DLC downregulated CD14 and expressed CD1a. Importantly, both KG-1 and MUTZ-3-derived DLC promoted proliferation of allogeneic responder cells more efficiently than unmodified cells; neither cells incorporated FITC-labeled dextran, but both stimulated IFN-γ production from responding allogeneic CD8+ T cells. Control DC produced from PBMC using the FastDC culture also expressed high levels of critical cell surface ligands and demonstrated good APC function. This paper indicates that functional DLC can be cultured from the AML cell lines KG-1 and MUTZ-3, and FastDC culture generates functional KG-1 DLC.

  9. The KinFact intervention - a randomized controlled trial to increase family communication about cancer history.

    Science.gov (United States)

    Bodurtha, Joann N; McClish, Donna; Gyure, Maria; Corona, Rosalie; Krist, Alexander H; Rodríguez, Vivian M; Maibauer, Alisa M; Borzelleca, Joseph; Bowen, Deborah J; Quillin, John M

    2014-10-01

    Knowing family history is important for understanding cancer risk, yet communication within families is suboptimal. Providing strategies to enhance communication may be useful. Four hundred ninety women were recruited from urban, safety-net, hospital-based primary care women's health clinics. Participants were randomized to receive the KinFact intervention or the control handout on lowering risks for breast/colon cancer and screening recommendations. Cancer family history was reviewed with all participants. The 20-minute KinFact intervention, based in communication and behavior theory, included reviewing individualized breast/colon cancer risks and an interactive presentation about cancer and communication. Study outcomes included whether participants reported collecting family history, shared cancer risk information with relatives, and the frequency of communication with relatives. Data were collected at baseline, 1, 6, and 14 months. Overall, intervention participants were significantly more likely to gather family cancer information at follow-up (odds ratio [OR]: 2.73; 95% confidence interval [CI]: 2.01, 3.71) and to share familial cancer information with relatives (OR: 1.85; 95% CI: 1.37, 2.48). Communication frequency (1=not at all; 4=a lot) was significantly increased at follow-up (1.67 vs. 1.54). Differences were not modified by age, race, education, or family history. However, effects were modified by pregnancy status and genetic literacy. Intervention effects for information gathering and frequency were observed for nonpregnant women but not for pregnant women. Additionally, intervention effects were observed for information gathering in women with high genetic literacy, but not in women with low genetic literacy. The KinFact intervention successfully promoted family communication about cancer risk. Educating women to enhance their communication skills surrounding family history may allow them to partner more effectively with their families and ultimately

  10. Oncogenic RAS enables DNA damage- and p53-dependent differentiation of acute myeloid leukemia cells in response to chemotherapy.

    Directory of Open Access Journals (Sweden)

    Mona Meyer

    Full Text Available Acute myeloid leukemia (AML is a clonal disease originating from myeloid progenitor cells with a heterogeneous genetic background. High-dose cytarabine is used as the standard consolidation chemotherapy. Oncogenic RAS mutations are frequently observed in AML, and are associated with beneficial response to cytarabine. Why AML-patients with oncogenic RAS benefit most from high-dose cytarabine post-remission therapy is not well understood. Here we used bone marrow cells expressing a conditional MLL-ENL-ER oncogene to investigate the interaction of oncogenic RAS and chemotherapeutic agents. We show that oncogenic RAS synergizes with cytotoxic agents such as cytarabine in activation of DNA damage checkpoints, resulting in a p53-dependent genetic program that reduces clonogenicity and increases myeloid differentiation. Our data can explain the beneficial effects observed for AML patients with oncogenic RAS treated with higher dosages of cytarabine and suggest that induction of p53-dependent differentiation, e.g. by interfering with Mdm2-mediated degradation, may be a rational approach to increase cure rate in response to chemotherapy. The data also support the notion that the therapeutic success of cytotoxic drugs may depend on their ability to promote the differentiation of tumor-initiating cells.

  11. Linagliptin increases incretin levels, lowers glucagon, and improves glycemic control in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Rauch, Thomas; Graefe-Mody, Ulrike; Deacon, Carolyn F

    2012-01-01

    Linagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed...... with linagliptin. The effects of linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM....

  12. Nano-hole induction by nanodiamond and nanoplatinum liquid, DPV576, reverses multidrug resistance in human myeloid leukemia (HL60/AR

    Directory of Open Access Journals (Sweden)

    Ghoneum A

    2013-07-01

    Full Text Available Alia Ghoneum,1,2 Shivani Sharma,1,3 James Gimzewsk1,3 1Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, 2Department of Otalaryngology, Drew University of Medicine and Science, Los Angeles, 3California Nanosystems Institute (CNSI at University of California, Los Angeles, Los Angeles, CA, USA Abstract: Recently nanoparticles have been extensively studied and have proven to be a promising candidate for cancer treatment and diagnosis. In the current study, we examined the chemo-sensitizing activity of a mixture of nanodiamond (ND and nanoplatinum (NP solution known as DPV576, against multidrug-resistant (MDR human myeloid leukemia (HL60/AR and MDR-sensitive cells (HL60. Cancer cells were cultured with different concentrations of daunorubicin (DNR (1 × 10-9–1 × 10-6 M in the presence of selected concentrations of DPV576 (2.5%–10% v/v. Cancer cell survival was determined by MTT assay, drug accumulation by flow cytometry and confocal laser scanning microscopy (CLSM, and holes and structural changes by atomic force microscopy (AFM. Co-treatment of HL60/AR cells with DNR plus DPV576 resulted in the reduction of the IC50 to 1/4th. This was associated with increased incidences of holes inside the cells as compared with control untreated cells. On the other hand, HL60 cells did not show changes in their drug accumulation post-treatment with DPV576 and DNR. We conclude that DPV576 is an effective chemo-sensitizer as indicated by the reversal of HL60/AR cells to DNR and may represent a potential novel adjuvant for the treatment of chemo-resistant human myeloid leukemia. Keywords: nanodiamond, nanoplatinum, daunorubicin, flow cytometry, AFM

  13. Smart trick at the border. Latitudinal control transformer increases import capacity

    International Nuclear Information System (INIS)

    Roggen, M.

    2002-01-01

    Starting in June 2002, energy consumers in the Netherlands can get more electric power from abroad. Without expensive system extensions, TenneT now has some 1000 MW of extra capacity available. And that is not all. Two latitudinal control transformers are able to control the capacity of the link as desired: 16 positions for import, and 16 for export [nl

  14. Ride Control Systems - Reduced Motions on the Cost of Increased Sectional Forces ?

    DEFF Research Database (Denmark)

    Folsø, R.; Nielsen, Ulrik Dam; Torti, F.

    2003-01-01

    Implementation of passive and active ride control systems into both linear frequency and non-linear time domain strip theories is described. The ride control systems considered can consist of T-foils, fins or a combination of these. These appendages are taken into account by considering the lift...

  15. Dasatinib accelerates valproic acid-induced acute myeloid leukemia cell death by regulation of differentiation capacity.

    Directory of Open Access Journals (Sweden)

    Sook-Kyoung Heo

    Full Text Available Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.

  16. ATM facilitates mouse gammaherpesvirus reactivation from myeloid cells during chronic infection.

    Science.gov (United States)

    Kulinski, Joseph M; Darrah, Eric J; Broniowska, Katarzyna A; Mboko, Wadzanai P; Mounce, Bryan C; Malherbe, Laurent P; Corbett, John A; Gauld, Stephen B; Tarakanova, Vera L

    2015-09-01

    Gammaherpesviruses are cancer-associated pathogens that establish life-long infection in most adults. Insufficiency of Ataxia-Telangiectasia mutated (ATM) kinase leads to a poor control of chronic gammaherpesvirus infection via an unknown mechanism that likely involves a suboptimal antiviral response. In contrast to the phenotype in the intact host, ATM facilitates gammaherpesvirus reactivation and replication in vitro. We hypothesized that ATM mediates both pro- and antiviral activities to regulate chronic gammaherpesvirus infection in an immunocompetent host. To test the proposed proviral activity of ATM in vivo, we generated mice with ATM deficiency limited to myeloid cells. Myeloid-specific ATM deficiency attenuated gammaherpesvirus infection during the establishment of viral latency. The results of our study uncover a proviral role of ATM in the context of gammaherpesvirus infection in vivo and support a model where ATM combines pro- and antiviral functions to facilitate both gammaherpesvirus-specific T cell immune response and viral reactivation in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Two Distinct Myeloid Subsets at the Term Human Fetal–Maternal Interface

    Directory of Open Access Journals (Sweden)

    Maria Laura Costa

    2017-10-01

    Full Text Available During pregnancy, immune cells infiltrate the placenta at different stages of fetal development. NK cells and macrophages are the most predominant cell types. These immune cells play pleiotropic roles, as they control spiral artery remodeling to ensure appropriate blood supply and maintain long-term tolerance to a true allograft; yet, they must be able to mount appropriate immune defenses to pathogens that may threaten the fetus. Whether the same cell type accomplishes all these tasks or if there are dedicated subsets remains controversial. Here, we identify and characterize two distinct subsets of myeloid cells that differ in their pro-inflammatory/regulatory capacity. While one subset predominantly produces the immune-modulating cytokine IL-10, the second subset has superior capacity to secrete pro-inflammatory mediators, such as IL-1β and IL-6. The putative regulatory myeloid cells also express high levels of inhibitory receptors and their ligands, including programmed cell death 1 (PD1 ligands. Importantly, a large fraction of CD8 and CD4 cells in normal term human placenta are PD1 positive, suggesting that the PD1/PD1 ligands axis might be critical to maintain tolerance during pregnancy.

  18. Significant yield increases from control of leaf diseases in maize - an overlooked problem?!

    DEFF Research Database (Denmark)

    Jørgensen, Lise Nistrup

    2012-01-01

    The area of maize has increased in several European countries in recent years. In Denmark, the area has increased from 10,000 ha in 1980 to 185,000 ha in 2011. Initially only silage maize was cultivated in Denmark, but in more recent years the area of grain maize has also increased. Farms growing...

  19. Increased risk of impulse control symptoms in Parkinson's disease with REM sleep behaviour disorder.

    Science.gov (United States)

    Fantini, M L; Macedo, L; Zibetti, M; Sarchioto, M; Vidal, T; Pereira, B; Marques, A; Debilly, B; Derost, P; Ulla, M; Vitello, N; Cicolin, A; Lopiano, L; Durif, F

    2015-02-01

    To assess the frequency of symptoms of impulse control disorders (ICD, namely pathological gambling, compulsive sexual behaviour, compulsive eating and compulsive shopping) and related behaviours (hobbyism, punding, walkabout and dopamine dysregulation syndrome) in patients with Parkinson's disease (PD) with and without probable rapid eye movement, sleep behaviour disorder (pRBD). Two hundred and sixteen consecutive PD patients, attending two university-based movement disorders clinics, were screened for p-RBD using the RBD Single Question and the RBD Screening Questionnaire (RBDSQ). Current ICDs and related behaviours symptoms were assessed with the Questionnaire for Impulsive-Compulsive Disorders in PD (QUIP)-short form. PD-pRBD patients (n=106/216;49%) had a longer PD duration, a higher Hoehn & Yahr score, a greater levodopa-equivalent daily dose (LEDD), but no difference in dopamine agonist use, compared to PD-without pRBD. A higher proportion of one or more current ICDs and related behaviours symptoms was reported in PD-pRBD compared to PD-without RBD (53% vs28%; p=0.0002). In a multivariate regression analysis accounting for gender, age of onset, PD duration, PD severity, depression score and total and dopaminergic agonist-LEDD, RBD was associated to a relative risk of 1.84 for any ICD or related behaviours symptoms (p=0.01), and to a risk of 2.59 for any ICD symptoms only (p=0.001). Furthermore, PD-pRBD had a more than fourfold risk for symptoms of pathological gambling (relative risk (RR): 4.87; p=0.049) compared to PD-without pRBD. The present study indicates that RBD is associated with an increased risk of developing symptoms of ICDs in PD. Identifying RBD in PD may help clinicians to choose the best therapeutic strategy. AU1023 Institutional Ethics Committee. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  20. Increased VLDL-triglyceride secretion precedes impaired control of endogenous glucose production in obese, normoglycemic men.

    Science.gov (United States)

    Sørensen, Lars P; Søndergaard, Esben; Nellemann, Birgitte; Christiansen, Jens S; Gormsen, Lars C; Nielsen, Søren

    2011-09-01

    To assess basal and insulin-mediated VLDL-triglyceride (TG) kinetics and the relationship between VLDL-TG secretion and hepatic insulin resistance assessed by endogenous glucose production (EGP) in obese and lean men. A total of 12 normoglycemic, obese (waist-to-hip ratio >0.9, BMI >30 kg/m(2)) and 12 lean (BMI 20-25 kg/m(2)) age-matched men were included. Ex vivo-labeled [1-(14)C]VLDL-TGs and [3-(3)H]glucose were infused postabsorptively and during a hyperinsulinemic-euglycemic clamp to determine VLDL-TG kinetics and EGP. Body composition was determined by dual X-ray absorptiometry and computed tomography scanning. Energy expenditure and substrate oxidation rates were measured by indirect calorimetry. Basal VLDL-TG secretion rates were increased in obese compared with lean men (1.25 ± 0.34 vs. 0.86 ± 0.34 μmol/kg fat-free mass [FFM]/min; P = 0.011), whereas there was no difference in clearance rates (150 ± 56 vs. 162 ± 77 mL/min; P = NS), resulting in greater VLDL-TG concentrations (0.74 ± 0.40 vs. 0.38 ± 0.20 mmol/L; P = 0.011). The absolute insulin-mediated suppression of VLDL-TG secretion was similar in the groups. However, the percentage reduction (-36 ± 18 vs. -54 ± 10%; P = 0.008) and achieved VLDL-TG secretion rates (0.76 ± 0.20 vs. 0.41 ± 0.19 μmol/kg FFM/min; P lean men (-17 ± 18 vs. 7 ± 20%; P = 0.007), resulting in less percentage reduction of VLDL-TG concentrations in obese men (-22 ± 20 vs. -56 ± 11%; P < 0.001). Insulin-suppressed EGP was similar (0.4 [0.0-0.8] vs. 0.1 [0.0-1.2] mg/kg FFM/min (median [range]); P = NS), and the percentage reduction was equivalent (-80% [57-98] vs. -98% [49-100], P = NS). Insulin-mediated glucose disposal was significantly reduced in obese men. Basal VLDL-TG secretion rates are increased in normoglycemic but insulin-resistant, obese men, resulting in hypertriglyceridemia. Insulin-mediated suppression of EGP is preserved in obese men, whereas suppression of VLDL-TG secretion is less pronounced in obese

  1. Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment

    NARCIS (Netherlands)

    Ortega-Gomez, Almudena; Salvermoser, Melanie; Rossaint, Jan; Pick, Robert; Brauner, Janine; Lemnitzer, Patricia; Tilgner, Jessica; de Jong, Renske J.; Megens, Remco T. A.; Jamasbi, Janina; Döring, Yvonne; Pham, Christine T.; Scheiermann, Christoph; Siess, Wolfgang; Drechsler, Maik; Weber, Christian; Grommes, Jochen; Zarbock, Alexander; Walzog, Barbara; Soehnlein, Oliver

    2016-01-01

    Therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis has been disappointing in clinical studies. Reasons for such failures include the lack of knowledge of arterial-specific recruitment patterns. Here we establish the importance of the cathepsin G (CatG) in the

  2. Real time capable control design with increased life expectancy for research purposes

    Science.gov (United States)

    Epple, S.; Jung, R.; Jalba, K.; Nasui, V.

    2017-05-01

    A new, freely programmable, scalable control system for academic research purposes was developed. The intention was, to have a control unit capable of handling multiple PT1000 temperature sensors at reasonable accuracy and temperature range, as well as digital input signals and providing more powerful output signals at 230V AC than conventional control units. To take full advantage of the system, control-loops are run in real time. The whole system runs independently of a personal computer. The two on-board RS232 connectors allow to connect further units to use more sensors or actuators or to connect other laboratory equipment, as required. To allow usage for long-time experiments, systematically electronic components with low failure-in-time (FIT) rate have been chosen in order to achieve high life expectancy. This paper describes the third prototype, which now provides stable measurements, and an improvement in accuracy compared to the previous designs. A rough estimation about the expected mean time between failures is given. As test case, a thermal solar system to produce hot tap water and assist heating in a single-family house was implemented. The solar fluid pump was power-controlled and several temperatures at different points in the hydraulic system were measured and used in the control algorithms. The hardware design proved suitable to test several different control strategies and their corresponding algorithms for the thermal solar system.

  3. Bilingualism increases neural response consistency and attentional control: evidence for sensory and cognitive coupling.

    Science.gov (United States)

    Krizman, Jennifer; Skoe, Erika; Marian, Viorica; Kraus, Nina

    2014-01-01

    Auditory processing is presumed to be influenced by cognitive processes - including attentional control - in a top-down manner. In bilinguals, activation of both languages during daily communication hones inhibitory skills, which subsequently bolster attentional control. We hypothesize that the heightened attentional demands of bilingual communication strengthens connections between cognitive (i.e., attentional control) and auditory processing, leading to greater across-trial consistency in the auditory evoked response (i.e., neural consistency) in bilinguals. To assess this, we collected passively-elicited auditory evoked responses to the syllable [da] in adolescent Spanish-English bilinguals and English monolinguals and separately obtained measures of attentional control and language ability. Bilinguals demonstrated enhanced attentional control and more consistent brainstem and cortical responses. In bilinguals, but not monolinguals, brainstem consistency tracked with language proficiency and attentional control. We interpret these enhancements in neural consistency as the outcome of strengthened attentional control that emerged from experience communicating in two languages. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. How the credit assignment problems in motor control could be solved after the cerebellum predicts increases in error.

    Science.gov (United States)

    Verduzco-Flores, Sergio O; O'Reilly, Randall C

    2015-01-01

    We present a cerebellar architecture with two main characteristics. The first one is that complex spikes respond to increases in sensory errors. The second one is that cerebellar modules associate particular contexts where errors have increased in the past with corrective commands that stop the increase in error. We analyze our architecture formally and computationally for the case of reaching in a 3D environment. In the case of motor control, we show that there are synergies of this architecture with the Equilibrium-Point hypothesis, leading to novel ways to solve the motor error and distal learning problems. In particular, the presence of desired equilibrium lengths for muscles provides a way to know when the error is increasing, and which corrections to apply. In the context of Threshold Control Theory and Perceptual Control Theory we show how to extend our model so it implements anticipative corrections in cascade control systems that span from muscle contractions to cognitive operations.

  5. How the credit assignment problems in motor control could be solved after the cerebellum predicts increases in error

    Directory of Open Access Journals (Sweden)

    Sergio Oscar Verduzco-Flores

    2015-03-01

    Full Text Available We present a cerebellar architecture with two main characteristics. The first one is that complex spikes respond to increases in sensory errors. The second one is that cerebellar modules associate particular contexts where errors have increased in the past with corrective commands that stop the increase in error. We analyze our architecture formally and computationally for the case of reaching in a 3D environment. In the case of motor control, we show that there are synergies of this architecture with the Equilibrium-Point hypothesis, leading to novel ways to solve the motor error and distal learning problems. In particular, the presence of desired equilibrium lengths for muscles provides a way to know when the error is increasing, and which corrections to apply. In the context of Threshold Control Theory and Perceptual Control Theory we show how to extend our model so it implements anticipative corrections in cascade control systems that span from muscle contractions to cognitive operations.

  6. Therapeutic Effects of Myeloid Cell Leukemia-1 siRNA on Human Acute Myeloid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Hadi Karami

    2014-05-01

    Full Text Available Purpose: Up-regulation of Mcl-1, a known anti-apoptotic protein, is associated with the survival and progression of various malignancies including leukemia. The aim of this study was to explore the effect of Mcl-1 small interference RNA (siRNA on the proliferation and apoptosis of HL-60 acute myeloid leukemia (AML cells. Methods: siRNA transfection was performed using Lipofectamine™2000 reagent. Relative mRNA and protein expressions were quantified by quantitative real-time PCR and Western blotting, respectively. Trypan blue assay was performed to assess tumor cell proliferation after siRNA transfection. The cytotoxic effect of Mcl-1 siRNA on leukemic cells was measured using MTT assay. Apoptosis was detected using ELISA cell death assay. Results: Mcl-1 siRNA clearly lowered both Mcl-1 mRNA and protein levels in a time-dependent manner, leading to marked inhibition of cell survival and proliferation. Furthermore, Mcl-1 down-regulation significantly enhanced the extent of HL-60 apoptotic cells. Conclusion: Our results suggest that the down-regulation of Mcl-1 by siRNA can effectively trigger apoptosis and inhibit the proliferation of leukemic cells. Therefore, Mcl-1 siRNA may be a potent adjuvant in AML therapy.

  7. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment

    OpenAIRE

    Dorhoi, Anca; Iannaccone, Marco; Farinacci, Maura; Faé, Kellen C.; Schreiber, Jörg; Moura-Alves, Pedro; Nouailles, Geraldine; Mollenkopf, Hans-Joachim; Oberbeck-Müller, Dagmar; Jörg, Sabine; Heinemann, Ellen; Hahnke, Karin; Löwe, Delia; Del Nonno, Franca; Goletti, Delia

    2013-01-01

    The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in...

  8. INFORMATION SYSTEMS: VA Computer Control Weaknesses Increase Risk of Fraud, Misuse, and Improper Disclosure

    National Research Council Canada - National Science Library

    1998-01-01

    This report discusses weaknesses that we identified during our assessment of general computer controls that support key financial management and benefit delivery operations of the department of Veterans Affairs...

  9. Air Traffic Control: Immature Software Acquisition Processes Increase FAA System Acquisition Risks

    Science.gov (United States)

    1997-03-01

    The General Accounting Office (GAO) at the request of Congress reviewed (1) : the maturity of Federal Aviation Administration's (FAA's) Air Traffic Control : (ATC) modernization software acquisition processes, and (2) the steps/actions : FAA has unde...

  10. Multi-Temperature Zone, Droplet-based Microreactor for Increased Temperature Control in Nanoparticle Synthesis

    KAUST Repository

    Erdem, E. Yegâ n; Cheng, Jim C.; Doyle, Fiona M.; Pisano, Albert P.

    2013-01-01

    Microreactors are an emerging technology for the controlled synthesis of nanoparticles. The Multi-Temperature zone Microreactor (MTM) described in this work utilizes thermally isolated heated and cooled regions for the purpose of separating

  11. Does increased postural threat lead to more conscious control of posture?

    Science.gov (United States)

    Huffman, J L; Horslen, B C; Carpenter, M G; Adkin, A L

    2009-11-01

    Although it is well established that postural threat modifies postural control, little is known regarding the underlying mechanism(s) responsible for these changes. It is possible that changes in postural control under conditions of elevated postural threat result from a shift to a more conscious control of posture. The purpose of this study was to determine the influence of elevated postural threat on conscious control of posture and to determine the relationship between conscious control and postural control measures. Forty-eight healthy young adults stood on a force plate at two different surface heights: ground level (LOW) and 3.2-m above ground level (HIGH). Centre of pressure measures calculated in the anterior-posterior (AP) direction were mean position (AP-MP), root mean square (AP-RMS) and mean power frequency (AP-MPF). A modified state-specific version of the Movement Specific Reinvestment Scale was used to measure conscious motor processing (CMP) and movement self-consciousness (MSC). Balance confidence, fear of falling, perceived stability, and perceived and actual anxiety indicators were also collected. A significant effect of postural threat was found for movement reinvestment as participants reported more conscious control and a greater concern about their posture at the HIGH height. Significant correlations between CMP and MSC with AP-MP were observed as participants who consciously controlled and were more concerned for their posture leaned further away from the platform edge. It is possible that changes in movement reinvestment can influence specific aspects of posture (leaning) but other aspects may be immune to these changes (amplitude and frequency).

  12. Insight into the Physical and Dynamical Processes that Control Rapid Increases in Total Flash Rate

    Science.gov (United States)

    Schultz, Christopher J.; Carey, Lawrence D.; Schultz, Elise V.; Blakeslee, Richard J.; Goodman, Steven J.

    2015-01-01

    Rapid increases in total lightning (also termed "lightning jumps") have been observed for many decades. Lightning jumps have been well correlated to severe and hazardous weather occurrence. The main focus of lightning jump work has been on the development of lightning algorithms to be used in real-time assessment of storm intensity. However, in these studies it is typically assumed that the updraft "increases" without direct measurements of the vertical motion, or specification of which updraft characteristic actually increases (e.g., average speed, maximum speed, or convective updraft volume). Therefore, an end-to-end physical and dynamical basis for coupling rapid increases in total flash rate to increases in updraft speed and volume must be understood in order to ultimately relate lightning occurrence to severe storm metrics. Herein, we use polarimetric, multi-Doppler, and lightning mapping array measurements to provide physical context as to why rapid increases in total lightning are closely tied to severe and hazardous weather.

  13. Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia.

    Science.gov (United States)

    Kotini, Andriana G; Chang, Chan-Jung; Chow, Arthur; Yuan, Han; Ho, Tzu-Chieh; Wang, Tiansu; Vora, Shailee; Solovyov, Alexander; Husser, Chrystel; Olszewska, Malgorzata; Teruya-Feldstein, Julie; Perumal, Deepak; Klimek, Virginia M; Spyridonidis, Alexandros; Rampal, Raajit K; Silverman, Lewis; Reddy, E Premkumar; Papaemmanuil, Elli; Parekh, Samir; Greenbaum, Benjamin D; Leslie, Christina S; Kharas, Michael G; Papapetrou, Eirini P

    2017-03-02

    Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

    Science.gov (United States)

    Papaspyridonos, Marianna; Matei, Irina; Huang, Yujie; do Rosario Andre, Maria; Brazier-Mitouart, Helene; Waite, Janelle C; Chan, April S; Kalter, Julie; Ramos, Ilyssa; Wu, Qi; Williams, Caitlin; Wolchok, Jedd D; Chapman, Paul B; Peinado, Hector; Anandasabapathy, Niroshana; Ocean, Allyson J; Kaplan, Rosandra N; Greenfield, Jeffrey P; Bromberg, Jacqueline; Skokos, Dimitris; Lyden, David

    2015-04-29

    A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis.

  15. Radotinib Induces Apoptosis of CD11b+ Cells Differentiated from Acute Myeloid Leukemia Cells.

    Directory of Open Access Journals (Sweden)

    Sook-Kyoung Heo

    Full Text Available Radotinib, developed as a BCR/ABL tyrosine kinase inhibitor (TKI, is approved for the second-line treatment of chronic myeloid leukemia (CML in South Korea. However, therapeutic effects of radotinib in acute myeloid leukemia (AML are unknown. In the present study, we demonstrate that radotinib significantly decreases the viability of AML cells in a dose-dependent manner. Kasumi-1 cells were more sensitive to radotinib than NB4, HL60, or THP-1 cell lines. Furthermore, radotinib induced CD11b expression in NB4, THP-1, and Kasumi-1 cells either in presence or absence of all trans-retinoic acid (ATRA. We found that radotinib promoted differentiation and induced CD11b expression in AML cells by downregulating LYN. However, CD11b expression induced by ATRA in HL60 cells was decreased by radotinib through upregulation of LYN. Furthermore, radotinib mainly induced apoptosis of CD11b+ cells in the total population of AML cells. Radotinib also increased apoptosis of CD11b+ HL60 cells when they were differentiated by ATRA/dasatinib treatment. We show that radotinib induced apoptosis via caspase-3 activation and the loss of mitochondrial membrane potential (ΔΨm in CD11b+ cells differentiated from AML cells. Our results suggest that radotinib may be used as a candidate drug in AML or a chemosensitizer for treatment of AML by other therapeutics.

  16. The myeloid receptor PILRβ mediates the balance of inflammatory responses through regulation of IL-27 production.

    Directory of Open Access Journals (Sweden)

    Cristina M Tato

    Full Text Available Paired immunoglobulin-like receptors beta, PILRβ, and alpha, PILRα, are related to the Siglec family of receptors and are expressed primarily on cells of the myeloid lineage. PILRβ is a DAP12 binding partner expressed on both human and mouse myeloid cells. The potential ligand, CD99, is found on many cell types, such as epithelial cells where it plays a role in migration of immune cells to sites of inflammation. Pilrb deficient mice were challenged with the parasite Toxoplasma gondii in two different models of infection induced inflammation; one involving the establishment of chronic encephalitis and a second mimicking inflammatory bowel disease in order to understand the potential role of this receptor in persistent inflammatory responses. It was found that in the absence of activating signals from PILRβ, antigen-presenting cells (APCs produced increased amounts of IL-27, p28 and promoted IL-10 production in effector T cells. The sustained production of IL-27 led ultimately to enhanced survival after challenge due to dampened immune pathology in the gut. Similar protection was also observed in the CNS during chronic T. gondii infection after i.p. challenge again providing evidence that PILRβ is important for regulating aberrant inflammatory responses.

  17. Granulocytic sarcoma in a patient with chronic myeloid leukaemia in complete haematological, cytogenetic and molecular remission.

    Science.gov (United States)

    Kittai, Adam; Yu, Eun-Mi; Tabbara, Imad

    2014-12-23

    Granulocytic sarcoma, also known as myeloid sarcoma, is an extramedullary tumour composed of immature myeloid cells. Granulocytic sarcoma is typically found in patients with acute myeloid leukaemia, accelerated phase or blast crisis of chronic myeloid leukaemia, myelodysplastic syndrome, or as an isolated event without bone marrow involvement. We present a case of granulocytic sarcoma in a patient with chronic myeloid leukaemia in the setting of complete haematological, molecular and cytogenetic remission. Our patient was first treated with imatinib for chronic-phase chronic myeloid leukaemia. After maintaining remission for 42 months, he developed a granulocytic sarcoma in his spine. In this case report, we describe our case, along with the three other cases reported in the literature. In addition to being a rare diagnosis, this case demonstrates the importance of being vigilant in diagnosing the cause of back pain and atypical symptoms in patients with a history of leukaemia. 2014 BMJ Publishing Group Ltd.

  18. The role of peptide and DNA vaccines in myeloid leukemia immunotherapy

    Directory of Open Access Journals (Sweden)

    Lin Chen

    2013-02-01

    Full Text Available Abstract While chemotherapy and targeted therapy are successful in inducing the remission of myeloid leukemia as acute myeloid leukemia (AML and chronic myeloid leukemia (CML, the disease remains largely incurable. This observation is likely due to the drug resistance of leukemic cells, which are responsible for disease relapse. Myeloid leukemia vaccines may most likely be beneficial for eradicating minimal residual disease after treatment with chemotherapy or targeted therapy. Several targeted immunotherapies using leukemia vaccines have been heavily investigated in clinical and preclinical trials. This review will focus on peptides and DNA vaccines in the context of myeloid leukemias, and optimal strategies for enhancing the efficacy of vaccines based on myeloid leukemia immunization are also summarized.

  19. [Statistical Process Control (SPC) can help prevent treatment errors without increasing costs in radiotherapy].

    Science.gov (United States)

    Govindarajan, R; Llueguera, E; Melero, A; Molero, J; Soler, N; Rueda, C; Paradinas, C

    2010-01-01

    Statistical Process Control (SPC) was applied to monitor patient set-up in radiotherapy and, when the measured set-up error values indicated a loss of process stability, its root cause was identified and eliminated to prevent set-up errors. Set up errors were measured for medial-lateral (ml), cranial-caudal (cc) and anterior-posterior (ap) dimensions and then the upper control limits were calculated. Once the control limits were known and the range variability was acceptable, treatment set-up errors were monitored using sub-groups of 3 patients, three times each shift. These values were plotted on a control chart in real time. Control limit values showed that the existing variation was acceptable. Set-up errors, measured and plotted on a X chart, helped monitor the set-up process stability and, if and when the stability was lost, treatment was interrupted, the particular cause responsible for the non-random pattern was identified and corrective action was taken before proceeding with the treatment. SPC protocol focuses on controlling the variability due to assignable cause instead of focusing on patient-to-patient variability which normally does not exist. Compared to weekly sampling of set-up error in each and every patient, which may only ensure that just those sampled sessions were set-up correctly, the SPC method enables set-up error prevention in all treatment sessions for all patients and, at the same time, reduces the control costs. Copyright © 2009 SECA. Published by Elsevier Espana. All rights reserved.

  20. Intraoperative tight glucose control using hyperinsulinemic normoglycemia increases delirium after cardiac surgery.

    Science.gov (United States)

    Saager, Leif; Duncan, Andra E; Yared, Jean-Pierre; Hesler, Brian D; You, Jing; Deogaonkar, Anupa; Sessler, Daniel I; Kurz, Andrea

    2015-06-01

    Postoperative delirium is common in patients recovering from cardiac surgery. Tight glucose control has been shown to reduce mortality and morbidity. Therefore, the authors sought to determine the effect of tight intraoperative glucose control using a hyperinsulinemic-normoglycemic clamp approach on postoperative delirium in patients undergoing cardiac surgery. The authors enrolled 198 adult patients having cardiac surgery in this randomized, double-blind, single-center trial. Patients were randomly assigned to either tight intraoperative glucose control with a hyperinsulinemic-normoglycemic clamp (target blood glucose, 80 to 110 mg/dl) or standard therapy (conventional insulin administration with blood glucose target, battery. The authors considered patients to have experienced postoperative delirium when Confusion Assessment Method testing was positive at any assessment. A positive Confusion Assessment Method was defined by the presence of features 1 (acute onset and fluctuating course) and 2 (inattention) and either 3 (disorganized thinking) or 4 (altered consciousness). Patients randomized to tight glucose control were more likely to be diagnosed as being delirious than those assigned to routine glucose control (26 of 93 vs. 15 of 105; relative risk, 1.89; 95% CI, 1.06 to 3.37; P = 0.03), after adjusting for preoperative usage of calcium channel blocker and American Society of Anesthesiologist physical status. Delirium severity, among patients with delirium, was comparable with each glucose management strategy. Intraoperative hyperinsulinemic-normoglycemia augments the risk of delirium after cardiac surgery, but not its severity.

  1. Recurrence of acute myeloid leukemia in cryptorchid testis: case report

    International Nuclear Information System (INIS)

    Góes, Luccas Santos Patto de; Lopes, Roberto Iglesias; Campos, Octavio Henrique Arcos; Oliveira, Luiz Carlos Neves de; Sant'Anna, Alexandre Crippa; Dall'Oglio, Marcos Francisco; Srougi, Miguel

    2014-01-01

    A 23-year-old male with a history of bone marrow transplant for acute myeloid leukemia. He presented a large mass in the right inguinal region 5 years ago. Upon physical examination, right-sided cryptorchidism was observed. The tumor markers alpha-fetoprotein and beta-HCG were within normalcy range and lactate dehydrogenase was raised. Computed tomography of the abdomen and pelvis revealed right testicular mass in contiguity with the inguinal canal to the ipsilateral retroperitoneum, associated with right hydronephrosis. Due to the risk of germ-cell tumor in undescended testicle, the patient underwent radical right orchiectomy. The pathological examination showed recurrence of acute myeloid leukemia in the testis. He was referred to oncology for adjuvant therapy. Our literature review found no similar cases described

  2. Myeloid derived suppressor cells as therapeutic target in hematological malignancies

    Directory of Open Access Journals (Sweden)

    Kim eDe Veirman

    2014-12-01

    Full Text Available Myeloid derived suppressor cells (MDSC are a heterogeneous population of immature myeloid cells that accumulate during pathological conditions such as cancer and are associated with a poor clinical outcome. MDSC expansion hampers the host anti-tumor immune response by inhibition of T cell proliferation, cytokine secretion and recruitment of regulatory T cells. In addition, MDSC exert non-immunological functions including the promotion of angiogenesis, tumor invasion and metastasis. Recent years, MDSC are considered as a potential target in solid tumors and hematological malignancies to enhance the effects of currently used immune modulating agents. This review focuses on the characteristics, distribution, functions, cell-cell interactions and targeting of MDSC in hematological malignancies including multiple myeloma, lymphoma and leukemia.

  3. Myeloid cells in Alzheimer's disease: culprits, victims or innocent bystanders?

    Science.gov (United States)

    Meyer-Luehmann, Melanie; Prinz, Marco

    2015-10-01

    Several recent genome-wide association studies (GWAS) in patients with neurodegenerative disorders have shed new light on the brain immune system, suggesting that it plays a pivotal role in disease pathogenesis. Mononuclear phagocytes are blatantly involved in Alzheimer's disease (AD) of the central nervous system (CNS), but the specific functions of resident microglia, perivascular or meningeal macrophages, and circulating myeloid cells have not yet been fully resolved. Next-generation sequencing, high-throughput immune profiling technologies, and novel genetic tools have recently revolutionized the characterization of innate immune responses during AD. These studies advocate selective and non-redundant roles for myeloid subsets, which could be a target for novel disease-modifying therapies in AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Induction chemotherapy in acute myeloid leukaemia: origins and emerging directions.

    Science.gov (United States)

    Upadhyay, Vivek A; Fathi, Amir T

    2018-03-01

    This review summarizes the hallmark developments in induction chemotherapy for acute myeloid leukaemia and further describes future directions in its evolution. We describe the origin of induction chemotherapy. We also describe notable modifications and adjustments to 7+3 induction chemotherapy since its development. Finally, we describe new efforts to modify and add new agents to induction therapy, including '7+3 Plus' combinations. Induction chemotherapy remains the standard of care for the majority of patients with acute myeloid leukaemia. However, its success is limited in a subset of patients by toxicity, failure to achieve remission and potential for subsequent relapse. Novel agents such as mutant fms like tyrosine kinase 3 inhibitors, mutant isocitrate dehydrogenase inhibitors, CD33-antibody drug conjugates and liposomal formulations have demonstrated significant potential as modifications to traditional induction chemotherapy.

  5. Recurrence of acute myeloid leukemia in cryptorchid testis: case report

    Energy Technology Data Exchange (ETDEWEB)

    Góes, Luccas Santos Patto de [Hospital do Servidor Público Municipal de São Paulo, São Paulo, SP (Brazil); Lopes, Roberto Iglesias [Hospital do Servidor Público Municipal de São Paulo, São Paulo, SP (Brazil); Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Campos, Octavio Henrique Arcos [Hospital do Servidor Público Municipal de São Paulo, São Paulo, SP (Brazil); Oliveira, Luiz Carlos Neves de; Sant' Anna, Alexandre Crippa; Dall' Oglio, Marcos Francisco; Srougi, Miguel [Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-07-01

    A 23-year-old male with a history of bone marrow transplant for acute myeloid leukemia. He presented a large mass in the right inguinal region 5 years ago. Upon physical examination, right-sided cryptorchidism was observed. The tumor markers alpha-fetoprotein and beta-HCG were within normalcy range and lactate dehydrogenase was raised. Computed tomography of the abdomen and pelvis revealed right testicular mass in contiguity with the inguinal canal to the ipsilateral retroperitoneum, associated with right hydronephrosis. Due to the risk of germ-cell tumor in undescended testicle, the patient underwent radical right orchiectomy. The pathological examination showed recurrence of acute myeloid leukemia in the testis. He was referred to oncology for adjuvant therapy. Our literature review found no similar cases described.

  6. Secondary Leukemia in a non-Hodgkin's Lymphoma Patient Presenting as Myeloid Sarcoma of the Breast

    Directory of Open Access Journals (Sweden)

    Vincenzo Pitini

    2011-01-01

    Full Text Available As defined by the World Health Organization classification of tumors of hematopoietic and lymphoid tissue, myeloid sarcoma (MS is a tumor mass of myeloblasts or immature myeloid cells that can arise before, concurrent with, or following acute myeloid leukaemia. We describe a case of secondary leukemia presenting itself as MS of the breast in a patient previously treated for a non-Hodgkin's Lymphoma.

  7. Neutron control of well debit increasing by acoustic influence on oil formation

    International Nuclear Information System (INIS)

    Bogdanovich, B.Yu.; Nesterovich, A.V.; Khasaya, D.R.; Shikanov, A.E.; Shikanov, E.A.; Il'inskiy, A.V.; Mihailov, L.V.; Kolomiets, N.F.

    2012-01-01

    The effectiveness of the A E direction in oil reservoirs can be improved by controlling the parameters of the processes occurring before and after acoustic effect in oil reservoirs, followed by a choice of intervals stimulation of oil. Measurements of changes in these processes in the reservoir are made remotely via a metal pipe casing that requires the use of transparent methods of control. In implementing the method of pulse neutron-neutron logging in the study area provide periodic field impulse of fast neutrons emitted by the accelerating tube, resulting in leakage to its target nuclear reaction T (d, n) 4He

  8. Recurrence of acute myeloid leukemia in cryptorchid testis: case report

    OpenAIRE

    Góes, Luccas Santos Patto de; Lopes, Roberto Iglesias; Campos, Octavio Henrique Arcos; Oliveira, Luiz Carlos Neves de; Sant’Anna, Alexandre Crippa; Dall’Oglio, Marcos Francisco; Srougi, Miguel

    2014-01-01

    A 23-year-old male with a history of bone marrow transplant for acute myeloid leukemia. He presented a large mass in the right inguinal region 5 years ago. Upon physical examination, right-sided cryptorchidism was observed. The tumor markers alpha-fetoprotein and beta-HCG were within normalcy range and lactate dehydrogenase was raised. Computed tomography of the abdomen and pelvis revealed right testicular mass in contiguity with the inguinal canal to the ipsilateral retroperitoneum, associat...

  9. Trisomy 10 in acute myeloid leukemia: three new cases.

    Science.gov (United States)

    Llewellyn, I E; Morris, C M; Stanworth, S; Heaton, D C; Spearing, R L

    2000-04-15

    Trisomy 10 is a rare nonrandom cytogenetic abnormality found in association with acute myeloid leukemia (AML). The hematological and clinical features associated with this finding have not yet been clearly defined. A literature review revealed 13 cases of trisomy 10 in AML, some reported as a minority component of a more comprehensive AML study and therefore lacking a full description of both clinical and hematological features. We present a summary of these reports and add three new cases to the literature.

  10. Allogeneic stem cell transplantation in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Natasha Ali

    2012-11-01

    Full Text Available We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients. Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0±11.3 months, overall survival was 16%.

  11. Mildly disabled persons with multiple sclerosis use similar net joint power strategies as healthy controls when walking speed increases

    DEFF Research Database (Denmark)

    Brincks, John; Sørensen, Henrik; Dalgas, Ulrik

    2018-01-01

    flexors in mildly disabled persons with MS and healthy controls at different walking speeds. METHODS:Thirteen persons with MS and thirteen healthy controls participated and peak net joint power was calculated using 3D motion analysis. RESULTS:In general, no differences were found between speed......-matched healthy controls and persons with MS, but the fastest walking speed was significantly higher in healthy controls (2.42 m/s vs. 1.70 m/s). The net joint power increased in hip flexors, hip extensors, hip abductors, knee extensors and plantar flexors in both groups, when walking speed increased. Significant...... correlations between changes in walking speed and changes in net joint power of plantar flexors, hip extensors and hip flexors existed in healthy controls and persons with MS, and in net knee extensor absorption power of persons with MS only. CONCLUSION:In contrast to previous studies, these findings suggest...

  12. The Operations Intent and Effects Model: A Command and Control Methodology for Increased Automation

    Science.gov (United States)

    2013-06-01

    Command and Control Process (Curts and Cambell , 2006), in that an order describes Actions that cause Effects. The Effects in turn change the Current...Interoperability Workshop. Orlando, FL, USA, IEEE CS Press. Curts, R. J., Dr. & Cambell , D. E., Dr. (2006) “Rethinking Command & Control”. Paper 005

  13. Increased all-cause mortality with use of psychotropic medication in dementia patients and controls

    DEFF Research Database (Denmark)

    Jennum, Poul; Baandrup, Lone; Ibsen, Rikke

    2015-01-01

    compared with 44,286 control subjects with a minimum follow-up of four years and matched on age, gender, marital status, and community location. Information about psychotropic medication use (benzodiazepines, antidepressants, antipsychotics) was obtained from the Danish Medicinal Product Statistics. All...

  14. Using copper sulfate on hybrid striped bass eggs to control fungus and increase survival

    Science.gov (United States)

    A major obstacle in fish hatcheries is the inevitable fungal growth on eggs. Copper sulfate (CuSO4) is commonly used for fungus control in channel catfish hatcheries that use troughs, but effectiveness on fish eggs hatched using different systems has only recently been investigated. Fish were spawn...

  15. Anti-seismic air condition's cooling capability increase of the second control area

    International Nuclear Information System (INIS)

    Pan Qiang

    2008-01-01

    Secondary area (SCA) air-conditioning system is an important ventilation system in plant. It should achieve the indoor temperature controllable. To resolve the problem of cooling capacity insufficiency, on the basis of ventilation and refrigeration theory, the thesis analyzes the design modification plan. (author)

  16. Increasing Restorability for Local-to-Egress Restoration in GMPLS Controlled Networks with Limited Wavelength Conversion

    DEFF Research Database (Denmark)

    Ruepp, Sarah Renée; Buron, Jakob Due; Andriolli, N.

    2006-01-01

    We study the performance of the local-to-egress restoration method in GMPLS controlled optical networks, when a limited number of wavelength converters are available. We evaluate the recovery percentage for a converter-saving label assignment scheme and compare its performance to a simple scheme...

  17. The Effects of Fall-Risk-Increasing Drugs on Postural Control : A Literature Review

    NARCIS (Netherlands)

    de Groot, Maartje H.; van Campen, Jos P. C. M.; Moek, Marije A.; Tulner, Linda R.; Beijnen, Jos H.; Lamoth, Claudine J. C.

    Meta-analyses showed that psychotropic drugs (antidepressants, neuroleptics, benzodiazepines, antiepileptic drugs) and some cardiac drugs (digoxin, type IA anti-arrhythmics, diuretics) are associated with increased fall risk. Because balance and gait disorders are the most consistent predictors of

  18. Osteoclasts in multiple myeloma are derived from Gr-1+CD11b+myeloid-derived suppressor cells.

    Directory of Open Access Journals (Sweden)

    Junling Zhuang

    Full Text Available Osteoclasts play a key role in the development of cancer-associated osteolytic lesions. The number and activity of osteoclasts are often enhanced by tumors. However, the origin of osteoclasts is unknown. Myeloid-derived suppressor cells (MDSCs are one of the pre-metastatic niche components that are induced to expand by tumor cells. Here we show that the MDSCs can differentiate into mature and functional osteoclasts in vitro and in vivo. Inoculation of 5TGM1-GFP myeloma cells into C57BL6/KaLwRij mice led to a significant expansion of MDSCs in blood, spleen, and bone marrow over time. When grown in osteoclastogenic media in vitro, MDSCs from tumor-challenged mice displayed 14 times greater potential to differentiate into mature and functional osteoclasts than those from non-tumor controls. Importantly, MDSCs from tumor-challenged LacZ transgenic mice differentiated into LacZ+osteoclasts in vivo. Furthermore, a significant increase in tumor burden and bone loss accompanied by increased number of osteoclasts was observed in mice co-inoculated with tumor-challenged MDSCs and 5TGM1 cells compared to the control animals received 5TGM1 cells alone. Finally, treatment of MDSCs from myeloma-challenged mice with Zoledronic acid (ZA, a potent inhibitor of bone resorption, inhibited the number of osteoclasts formed in MDSC cultures and the expansion of MDSCs and bone lesions in mice. Collectively, these data provide in vitro and in vivo evidence that tumor-induced MDSCs exacerbate cancer-associated bone destruction by directly serving as osteoclast precursors.

  19. Control Of Motor Unit Firing During Step-Like Increases In Voluntary Force

    Directory of Open Access Journals (Sweden)

    Xiaogang eHu

    2014-09-01

    Full Text Available In most skeletal muscles, force is generated by a combination of motor unit (MU recruitment and increases in the firing rate of previously active MUs. Two contrasting patterns of firing rate organization have been reported. In the first pattern, the earliest recruited MUs reach the highest firing rates as force is increased, and later recruited MUs fire at lower rates. When firing rate of multiple MUs are superimposed, these rate trajectories form a concentric layered profile termed ‘onion skin’. In the second pattern, called ‘reverse onion skin’, later recruited MUs reach higher firing rates, and crossing of firing rate trajectories for recorded MUs is common (although such trajectories are assembled routinely from different trials. Our present study examined the firing rate organization of concurrently active MUs of the first dorsal interosseous muscle during serial, step-like increases in isometric abduction forces. We used a surface sensor array coupled with MU discrimination algorithms to characterize MU firing patterns. Our objective was to determine whether ‘onion skin’ profiles are contingent upon the force trajectory of the motor task, examined here using step-like increases of force output, and also whether they are manifested at different force levels.Our results revealed that the overall ‘onion skin’ firing rate profile was retained as the force level increased with each force step up to 15% MVC. However, the distribution of firing rates across MUs was compressed with increasing force, and overlapping firing rate of units were observed. This rate compression was largely due to rate saturation of the relatively high frequency discharging MUs.Our results reflect flexible firing patterns across MUs at different levels of excitation drive. It is also evident that many units did not follow all the step increases consistently. This failure to track firing rate increases at higher forces could be due to an intrinsically

  20. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.

    Science.gov (United States)

    Hattori, Ayuna; Tsunoda, Makoto; Konuma, Takaaki; Kobayashi, Masayuki; Nagy, Tamas; Glushka, John; Tayyari, Fariba; McSkimming, Daniel; Kannan, Natarajan; Tojo, Arinobu; Edison, Arthur S; Ito, Takahiro

    2017-05-25

    Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.

  1. Myeloid-Derived Suppressor Cells and Therapeutic Strategies in Cancer

    Directory of Open Access Journals (Sweden)

    Hiroshi Katoh

    2015-01-01

    Full Text Available Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs. Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients.

  2. Genomic rearrangement in radiation-induced murine myeloid leukemia

    International Nuclear Information System (INIS)

    Ishihara, Hiroshi

    1994-01-01

    After whole body irradiation of 3Gy X ray to C3H/He male mice, acute myeloid leukemia is induced at an incidence of 20 to 30% within 2 years. We have studied the mechanism of occurrence of this radiation-induced murine myeloid leukemia. Detection and isolation of genomic structural aberration which may be accumulated accompanied with leukemogenesis are helpful in analyzing the complicated molecular process from radiation damage to leukemogenesis. So, our research work was done in three phases. First, structures of previously characterized oncogenes and cytokine-related genes were analyzed, and abnormal structures of fms(protooncogene encoding M-CSF receptor gene)-related and myc-related genes were found in several leukemia cells. Additionally, genomic structural aberration of IL-3 gene was observed in some leukemia cells, so that construction of genomic libraries and cloning of the abnormal IL-3 genomic DNAs were performed to characterize the structure. Secondly, because the breakage of chromosome 2 that is frequently observed in myeloid leukemia locates in proximal position of IL-1 gene cluster in some cases, the copy number of IL-1 gene was determined and the gene was cloned. Lastly, the abnormal genome of leukemia cell was cloned by in-gel competence reassociation method. We discussed these findings and evaluated the analysis of the molecular process of leukemogenesis using these cloned genomic fragments. (author)

  3. 19-nor vitamin-D analogs: a new class of potent inhibitors of proliferation and inducers of differentiation of human myeloid leukemia cell lines.

    Science.gov (United States)

    Asou, H; Koike, M; Elstner, E; Cambell, M; Le, J; Uskokovic, M R; Kamada, N; Koeffler, H P

    1998-10-01

    We have studied the in vitro biological activities and mechanisms of action of 1,25-dihydroxyvitamin D3 (1,25D3) and nine potent 1,25D3 analogs on proliferation and differentiation of myeloid leukemia cell lines (HL-60, retinoic acid-resistant HL-60 [RA-res HL-60], NB4 and Kasumi-1). The common novel structural motiff for almost all the analogs included removal of C-19 (19-nor); each also had unsaturation of the side chain. All the compounds were potent; for example, the concentration of analogs producing a 50% clonal inhibition (ED50) ranged between 1 x 10(-9) to 4 x 10(-11) mol/L when using the HL-60 cell line. The most active compound [1, 25(OH)2-16,23E-diene-26-trifluoro-19-nor-cholecalciferol (Ro 25-9716)] had an ED50 of 4 x 10(-11) mol/L; in contrast, the 1,25D3 produced an ED50 of 10(-9) mol/L with the HL-60 target cells. Ro 25-9716 (10(-9) mol/L, 3 days) was a strong inducer of myeloid differentiation because it caused 92% of the HL-60 cells to express CD11b and 75% of these cells to reduce nitroblue tetrazolium (NBT). This compound (10(-8) mol/L, 4 days) also caused HL-60 cells to arrest in the G1 phase of the cell cycle (88% cells in G1 v 48% of the untreated control cells). The p27(kip-1), a cyclin-dependent kinase inhibitor which is important in blocking the cell cycle, was induced more quickly and potently by Ro 25-9716 (10(-7) mol/L, 0 to 5 days) than by 1,25D3, suggesting a possible mechanism by which these analogs inhibit proliferation of leukemic growth. The NB4 promyelocytic leukemia cells cultured with the Ro 25-9716 were also inhibited in their clonal proliferation (ED50, 5 x 10(-11) mol/L) and their expression of CD11b was enhanced (80% positive [10(-9) mol/L, 4 days] v 27% untreated NB4 cells). Moreover, the combination of Ro 25-9716 (10(-9) mol/L) and all-trans retinoic acid (ATRA, 10(-7) mol/L) induced 92% of the NB4 cells to reduce NBT, whereas only 26% of the cells became NBT positive after a similar exposure to the combination of 1,25D3

  4. Cold working room temperature increased moderate/severe qualitative work stressor risk in Air Traffic Controllers

    Directory of Open Access Journals (Sweden)

    Dewi Astuti

    2012-07-01

    Full Text Available Latar belakang: Pemandu lalu lintas udara (PLLU kemungkinan lebih besar terkena stresor kerja kualitatif. Tujuan penelitian untuk mengidentifikasi beberapa faktor yang berkaitan dengan stresor kerja kualitatif moderat (SBKL sedang di antara PLLU di Bandar Udara Internasional Soekarno-Hatta.Metode:  Studi  potong  lintang  dilakukan  pada  bulan  November 2008  dengan  subjek  PLLU  aktif  bekerja minimal  6  bulan. Penelitian  menggunakan  kuesioner  standar  survei  diagnostik stres  dan  kuesioner  stresor rumah tangga. Kuesioner diisi oleh subjek.Hasil: Subjek berumur 27-55 tahun terdiri dari 122 PLLU dengan SBKL sedang/berat dan serta 13 (9,6% PLLU dengan SBKL rendah. Model menunjukkan bahwa mereka yang merasa dibandingkan dengan yang tidak merasa suhu ruangan terlalu dingin mempunyai 11-lipat risiko SBKL sedang/berat [rasio odds suaian (ORa = 10,63: 95% interval kepercayaan (CI = 1,79-65,59]. Dibandingkan dengan subjek tanpa stresor ketaksaan peran, mereka yang mempunyai stresor ketaksaan peran sedang/berat berisiko 8,2-lipat SBKL sedang/berat (ORa = 8,23: 95% CI = 1,13-59,90. Di samping itu, mereka yang mempunyai stresor tanggung jawab sedang/berat mendapatkan dibandingkan dengan tanpa stesor ini 6,6-kali berisiko SBKL sedang/berat (ORa = 6,64: 95% CI = 1.13-38.85, Selanjutntya mereka yang mempunyai dibandingkan dengan yang tanpa stresor pengembangan karir sedang/berat mempunyai 3,7-kali risiko SBKL sedang/berat  (ORa = 3,67: 95% CI = 0.88-15.35; P = 0,075.Kesimpulan: Subjek LLU yang merasa suhu ruangan terlalu dingin, stresor ketaksaan peran, tanggung jawab personal dan pengembangan karir sedang/berat mengalami peningkatan risiko SBKL sedang/berat. (Health Science Indones 2011;2:58-65.AbstractBack ground: Air traffic controllers (ATCs have a high level of responsibility which may lead to qualitative work load stressor (QLWS. This study identified several risk factors related to moderate qualitative

  5. 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.

  6. Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity

    Science.gov (United States)

    Abooali, Maryam; Yasinska, Inna M.; Casely-Hayford, Maxwell A.; Berger, Steffen M.; Fasler-Kan, Elizaveta; Sumbayev, Vadim V.

    2015-01-01

    Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells. PMID:26384306

  7. Using Acceptance and Commitment Therapy to Increase Self-Compassion: A Randomized Controlled Trial.

    Science.gov (United States)

    Yadavaia, James E; Hayes, Steven C; Vilardaga, Roger

    2014-10-01

    Self-compassion has been shown to be related to several types of psychopathology, including traumatic stress, and has been shown to improve in response to various kinds of interventions. Current conceptualizations of self-compassion fit well with the psychological flexibility model, which underlies acceptance and commitment therapy (ACT). However, there has been no research on ACT interventions specifically aimed at self-compassion. This randomized trial therefore compared a 6-hour ACT-based workshop targeting self-compassion to a wait-list control. From pretreatment to 2-month follow-up, ACT was significantly superior to the control condition in self-compassion, general psychological distress, and anxiety. Process analyses revealed psychological flexibility to be a significant mediator of changes in self-compassion, general psychological distress, depression, anxiety, and stress. Exploratory moderation analyses revealed the intervention to be of more benefit in terms of depression, anxiety, and stress to those with greater trauma history.

  8. Erosion of stereochemical control with increasing nucleophilicity: O-glycosylation at the diffusion limit.

    Science.gov (United States)

    Beaver, Matthew G; Woerpel, K A

    2010-02-19

    Nucleophilic substitution reactions of 2-deoxyglycosyl donors indicated that the reactivity of the oxygen nucleophile has a significant impact on stereoselectivity. Employing ethanol as the nucleophile resulted in a 1:1 (alpha:beta) ratio of diastereomers under S(N)1-like reaction conditions. Stereoselective formation of the 2-deoxy-alpha-O-glycoside was only observed when weaker nucleophiles, such as trifluoroethanol, were employed. The lack of stereoselectivity observed in reactions of common oxygen nucleophiles can be attributed to reaction rates of the stereochemistry-determining step that approach the diffusion limit. In this scenario, both faces of the prochiral oxocarbenium ion are subject to nucleophilic addition to afford a statistical mixture of diastereomeric products. Control experiments confirmed that all nucleophilic substitution reactions were performed under kinetic control.

  9. Joint System Prognostics For Increased Efficiency And Risk Mitigation In Advanced Nuclear Reactor Instrumentation and Control

    Energy Technology Data Exchange (ETDEWEB)

    Donald D. Dudenhoeffer; Tuan Q. Tran; Ronald L. Boring; Bruce P. Hallbert

    2006-08-01

    The science of prognostics is analogous to a doctor who, based on a set of symptoms and patient tests, assesses a probable cause, the risk to the patient, and a course of action for recovery. While traditional prognostics research has focused on the aspect of hydraulic and mechanical systems and associated failures, this project will take a joint view in focusing not only on the digital I&C aspect of reliability and risk, but also on the risks associated with the human element. Model development will not only include an approximation of the control system physical degradation but also on human performance degradation. Thus the goal of the prognostic system is to evaluate control room operation; to identify and potentially take action when performance degradation reduces plant efficiency, reliability or safety.

  10. Multi-Temperature Zone, Droplet-based Microreactor for Increased Temperature Control in Nanoparticle Synthesis

    KAUST Repository

    Erdem, E. Yegân

    2013-12-12

    Microreactors are an emerging technology for the controlled synthesis of nanoparticles. The Multi-Temperature zone Microreactor (MTM) described in this work utilizes thermally isolated heated and cooled regions for the purpose of separating nucleation and growth processes as well as to provide a platform for a systematic study on the effect of reaction conditions on nanoparticle synthesis. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Addiction: Decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain's control circuit

    OpenAIRE

    Volkow, Nora D.; Wang, Gene-Jack; Fowler, Joanna S.; Tomasi, Dardo; Telang, Frank; Baler, Ruben

    2010-01-01

    Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and drug cues, stress reactivity, and (c) negative mood, and a weakened control circuit. Although initial experimentation with a drug of abuse is larg...

  12. Asbestos: a hidden player behind the cholangiocarcinoma increase? Findings from a case?control analysis

    OpenAIRE

    Brandi, Giovanni; Di Girolamo, Stefania; Farioli, Andrea; de Rosa, Francesco; Curti, Stefania; Pinna, Antonio Daniele; Ercolani, Giorgio; Violante, Francesco Saverio; Biasco, Guido; Mattioli, Stefano

    2013-01-01

    Purposes We conducted a case?control analysis to explore the association between occupational exposure to asbestos and cholangiocarcinoma (CC). Methods The study was based on historical data from 155 consecutive patients with CC [69 intrahepatic CC (ICC) and 86 extrahepatic CC (ECC)] referred to Sant?Orsola-Malpighi University Hospital between 2006 and 2010. The cases were individually matched by calendar period of birth, sex, and region of residence to historical hospital and population cont...

  13. Rare myeloid sarcoma/acute myeloid leukemia with adrenal mass after allogeneic mobilization peripheral blood stem cell transplantation

    International Nuclear Information System (INIS)

    Wang, Ya-Fei; Li, Qian; Xu, Wen-Gui; Xiao, Jian-Yu; Pang, Qing-Song; Yang, Qing; Zhang, Yi-Zuo

    2013-01-01

    Myeloid sarcoma (MS) is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia (AML). This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission. A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010. After one month, bone marrow biopsy and aspiration confirmed the diagnosis of AML. Allogeneic mobilization peripheral blood stem cell transplantation was performed, with the sister of the patient as donor, after complete remission (CR) was achieved by chemotherapy. Five months after treatment, an adrenal mass was detected by positron emission tomography-computed tomography (PET-CT). Radiotherapy was performed for the localized mass after a multidisciplinary team (MDT) discussion. The patient is still alive as of May 2013, with no evidence of recurrent MS or leukemia

  14. Music Training Increases Phonological Awareness and Reading Skills in Developmental Dyslexia: A Randomized Control Trial.

    Science.gov (United States)

    Flaugnacco, Elena; Lopez, Luisa; Terribili, Chiara; Montico, Marcella; Zoia, Stefania; Schön, Daniele

    2015-01-01

    There is some evidence for a role of music training in boosting phonological awareness, word segmentation, working memory, as well as reading abilities in children with typical development. Poor performance in tasks requiring temporal processing, rhythm perception and sensorimotor synchronization seems to be a crucial factor underlying dyslexia in children. Interestingly, children with dyslexia show deficits in temporal processing, both in language and in music. Within this framework, we test the hypothesis that music training, by improving temporal processing and rhythm abilities, improves phonological awareness and reading skills in children with dyslexia. The study is a prospective, multicenter, open randomized controlled trial, consisting of test, rehabilitation and re-test (ID NCT02316873). After rehabilitation, the music group (N = 24) performed better than the control group (N = 22) in tasks assessing rhythmic abilities, phonological awareness and reading skills. This is the first randomized control trial testing the effect of music training in enhancing phonological and reading abilities in children with dyslexia. The findings show that music training can modify reading and phonological abilities even when these skills are severely impaired. Through the enhancement of temporal processing and rhythmic skills, music might become an important tool in both remediation and early intervention programs.Trial Registration: ClinicalTrials.gov NCT02316873

  15. Music Training Increases Phonological Awareness and Reading Skills in Developmental Dyslexia: A Randomized Control Trial.

    Directory of Open Access Journals (Sweden)

    Elena Flaugnacco

    Full Text Available There is some evidence for a role of music training in boosting phonological awareness, word segmentation, working memory, as well as reading abilities in children with typical development. Poor performance in tasks requiring temporal processing, rhythm perception and sensorimotor synchronization seems to be a crucial factor underlying dyslexia in children. Interestingly, children with dyslexia show deficits in temporal processing, both in language and in music. Within this framework, we test the hypothesis that music training, by improving temporal processing and rhythm abilities, improves phonological awareness and reading skills in children with dyslexia. The study is a prospective, multicenter, open randomized controlled trial, consisting of test, rehabilitation and re-test (ID NCT02316873. After rehabilitation, the music group (N = 24 performed better than the control group (N = 22 in tasks assessing rhythmic abilities, phonological awareness and reading skills. This is the first randomized control trial testing the effect of music training in enhancing phonological and reading abilities in children with dyslexia. The findings show that music training can modify reading and phonological abilities even when these skills are severely impaired. Through the enhancement of temporal processing and rhythmic skills, music might become an important tool in both remediation and early intervention programs.Trial Registration: ClinicalTrials.gov NCT02316873

  16. Splenectomy Correlates With Increased Risk of Acute Pancreatitis: A Case-Control Study in Taiwan

    Science.gov (United States)

    Lai, Shih-Wei; Lin, Cheng-Li; Liao, Kuan-Fu

    2016-01-01

    Objective The objective of the study was to investigate the association between splenectomy and acute pancreatitis. Methods We conducted a case-control study using the database of the Taiwan National Health Insurance Program. We included 7666 subjects aged 20–84 years with first-time acute pancreatitis during the period of 1998–2011 as cases and 30 664 randomly selected subjects without acute pancreatitis as controls. Both cases and controls were matched for sex, age, and index year of acute pancreatitis diagnosis. The association of acute pancreatitis with splenectomy was examined using a multivariable unconditional logistic regression model and reported as an odds ratio and its 95% confidence interval (CI). Results After adjustment for covariables, the adjusted odds ratio of acute pancreatitis was 2.90 for subjects with splenectomy (95% CI, 1.39–6.05) compared with subjects without splenectomy. Conclusions Splenectomy is associated with acute pancreatitis. Further studies are necessary to clarify the underlying mechanism. PMID:27087607

  17. Electronic mode of control to obtain increased torque and improved power factor from an asynchronous machine

    NARCIS (Netherlands)

    Wyk, van J.D.

    1970-01-01

    It is indicated that, by changing the electronic switching mode of the rotor current of an induction machine, it is possible to operate the machine at improved (capacitive) power factors and increased torque, or conversely at lower effective current and capacitive power factors at rated torque.

  18. Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial

    Directory of Open Access Journals (Sweden)

    Joannes A.A. Reijers

    2015-08-01

    Interpretation: Single dose administration of trastuzumab in humans is associated with an immediate, transient extracellular volume increase, either as a primary or secondary (compensatory response, which can be detected easily using routine clinical assessments. Echocardiographic changes, both short and long term, could not be found after single dose administration to drug-naive patients.

  19. Direct load control for electricity supply and demand matching : increasing reliability of wind energy

    NARCIS (Netherlands)

    Hoeve ten, Marieke

    2009-01-01

    In Sweden as well as in The Netherlands energy policy is increasingly aiming at extending the use of renew-able sources. In accordance with the targets of the European Union, both countries have formulated national targets for the year 2020. For wind ener

  20. When Creativity Met Transfer: Increasing Creativity and Transfer by Controlling the Styles of Processing

    Science.gov (United States)

    Kaniel, Shlomo

    2013-01-01

    The primary purpose of this article is to combine both transfer of learning (hereafter, transfer) and creativity into similar processes that can increase the products of transfer and creativity. Both transfer and creativity operate within reciprocal relationships between memory storage and working memory. Moreover, they are also based on moving…

  1. How effective has tobacco tax increase been in the Gambia? A case study of tobacco control

    Science.gov (United States)

    Nargis, Nigar; Manneh, Yahya; Krubally, Bakary; Jobe, Baboucarr; Ouma, Ahmed E Ogwell; Tcha-Kondor, Noureiny; Blecher, Evan H

    2016-01-01

    Objectives The objective of the present study was to evaluate how effective tobacco tax increase has been in increasing price of tobacco products and reducing tobacco consumption in the Gambia. In addition, it tests the hypothesis that tobacco tax revenue grows while tobacco consumption decreases as a result of tax and price increase. Setting The study is designed at the macroeconomic level to examine the import of tobacco products and revenue collected from tobacco taxation in a low-income setting. Participants The participants of this study are the government officials employed in the Ministry of Finance and Economic Affairs (MoFEA), the Gambia and the Gambia Revenue Authority, who are in charge of planning and implementing the tobacco tax policy in the Gambia. Interventions The study includes 2 consecutive interventions in tobacco tax policy in the Gambia. The first intervention was moving the tax base for the uniform specific excise tax on cigarettes from weight to pack of cigarettes in 2013. The second intervention involved increasing the excise and the environmental tax on tobacco products in 2014. Primary and secondary outcome measures The primary outcome measures were the cost, insurance and freight value and the price of tobacco products. The secondary outcome measures included the import of tobacco products and tobacco tax revenue. Results In 2013–2014, the Gambia MoFEA raised the specific excise rate, which increased price, reduced consumption and generated significantly more government revenue from tobacco products. This is a clear evidence of the win-win outcome of raising tobacco tax. In addition, the Gambia has set the example of harmonising tax rates between tobacco products that reduces the substitution between tobacco products. Conclusions The Gambia presents the best practice in tobacco taxation. There is need for documenting more country-specific evidence on the win-win outcome of raising tobacco tax. PMID:27566626

  2. Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Juan Liu

    2016-04-01

    Full Text Available Although dasatinib is effective in most imatinib mesylate (IMT-resistant chronic myeloid leukemia (CML patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell line K562 (K562RIMT. Compared with K562 control cells, exsomal release, the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt/ mammalian target of rapamycin (mTOR signaling and autophagic activity were increased significantly in K562RIMT cells and mTOR-independent beclin-1/Vps34 signaling was shown to be involved in exosomal release in these cells. We found that Notch1 activation-mediated reduction of phosphatase and tensin homolog (PTEN was responsible for the increased Akt/mTOR activities in K562RIMT cells and treatment with Notch1 γ-secretase inhibitor prevented activation of Akt/mTOR. In addition, suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K, induced upregulation of p53 and caspase 3, and led to increase of apoptosis in K562RIMT cells. Inhibition of autophagy by spautin-1 or beclin-1 knockdown decreased exosomal release, but did not affect apoptosis in K562RIMT cells. In summary, in K562RIMT cells dasatinib promoted apoptosis through downregulation of Akt/mTOR activities, while preventing exosomal release and inhibiting autophagy by downregulating expression of beclin-1 and Vps34. Our findings reveal distinct dasatinib-induced mechanisms of apoptotic response and exosomal release in imatinib-resistant CML cells.

  3. Progress Towards Increased Understanding and Control of Internal Transport Barriers on DIII-D

    Energy Technology Data Exchange (ETDEWEB)

    Doyle, E. J. [University of California, Los Angeles; Greenfield, C. M. [General Atomics; Austin, M. E. [University of Texas, Austin; Baylor, Larry R [ORNL; Burrell, K. H. [General Atomics; Casper, T. A. [Lawrence Livermore National Laboratory (LLNL); DeBoo, J. C. [General Atomics; Ernst, D. R. [Princeton Plasma Physics Laboratory (PPPL); Fenzi, C. [University of Wisconsin, Madison; Gohil, P. [General Atomics; Groebner, R. J. [General Atomics; Heidbrink, W. W. [University of California, Irvine; Jackson, G. L. [General Atomics; Jernigan, Thomas C [ORNL; Kinsey, J. E. [Lehigh University, Bethlehem, PA; Lao, L. L. [General Atomics; Makowski, M. A. [Lawrence Livermore National Laboratory (LLNL); Mckee, G. R. [University of Wisconsin, Madison; Murakami, Masanori [ORNL; Peebles, W. A. [University of California, Los Angeles; Prater, R. [General Atomics; Rettig, C. L. [University of California, Los Angeles; Rhodes, T. L. [University of California, Los Angeles; Rost, J. C. [Massachusetts Institute of Technology (MIT); Staebler, G. M. [General Atomics; Stallard, B. W. [Lawrence Livermore National Laboratory (LLNL); Strait, E. J. [General Atomics; Synakowski, E. J. [Princeton Plasma Physics Laboratory (PPPL); Thomas, D. M. [General Atomics; Wade, Mickey R [ORNL; Waltz, R. E. [General Atomics; Zeng, L. [University of California, Los Angeles

    2001-01-01

    Substantial progress has been made towards both understanding and control of internal transport barriers (ITBs) on DIII-D, resulting in the discovery of a new sustained high performance operating mode termed the Quiescent Double-Barrier (QDB) regime. The QDB regime combines core transport barriers with a quiescent, ELM-free H-mode edge (termed QH-mode), giving rise to separate (double) core and edge transport barriers. The core and edge barriers are mutually compatible and do not merge, resulting in broad core profiles with an edge pedestal. The QH-mode edge is characterized by ELM-free behavior with continuous multiharmonic MHD activity in the pedestal region, and has provided density and impurity control for 3.5 s (>20 τE) with divertor pumping. QDB plasmas are long-pulse high-performance candidates, having maintained a βNH89 product of 7 for 5 energy confinement times (Ti ≤ 16 keV, βN ≤ 2.9, H89 ≤ 2.4, τE ≤ 150 ms, DD neutron rate Sn ≤ 4x1015 s-1). The QDB regime has only been obtained in counter-NBI discharges (injection anti-parallel to plasma current) with divertor pumping. Other results include successful expansion of the ITB radius using (separately) both impurity injection and counter-NBI, and the formation of ITBs in the electron thermal channel using both ECH and strong negative central shear (NCS) at high power. These results are interpreted within a theoretical framework in which turbulence suppression is the key to ITB formation and control, and a decrease in core turbulence is observed in all cases of ITB formation.

  4. False discovery rate control incorporating phylogenetic tree increases detection power in microbiome-wide multiple testing.

    Science.gov (United States)

    Xiao, Jian; Cao, Hongyuan; Chen, Jun

    2017-09-15

    Next generation sequencing technologies have enabled the study of the human microbiome through direct sequencing of microbial DNA, resulting in an enormous amount of microbiome sequencing data. One unique characteristic of microbiome data is the phylogenetic tree that relates all the bacterial species. Closely related bacterial species have a tendency to exhibit a similar relationship with the environment or disease. Thus, incorporating the phylogenetic tree information can potentially improve the detection power for microbiome-wide association studies, where hundreds or thousands of tests are conducted simultaneously to identify bacterial species associated with a phenotype of interest. Despite much progress in multiple testing procedures such as false discovery rate (FDR) control, methods that take into account the phylogenetic tree are largely limited. We propose a new FDR control procedure that incorporates the prior structure information and apply it to microbiome data. The proposed procedure is based on a hierarchical model, where a structure-based prior distribution is designed to utilize the phylogenetic tree. By borrowing information from neighboring bacterial species, we are able to improve the statistical power of detecting associated bacterial species while controlling the FDR at desired levels. When the phylogenetic tree is mis-specified or non-informative, our procedure achieves a similar power as traditional procedures that do not take into account the tree structure. We demonstrate the performance of our method through extensive simulations and real microbiome datasets. We identified far more alcohol-drinking associated bacterial species than traditional methods. R package StructFDR is available from CRAN. chen.jun2@mayo.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  5. Progress towards increased understanding and control of internal transport barriers (ITBs) on DIII-D

    International Nuclear Information System (INIS)

    Doyle, E.J.; Greenfield, C.M.; Austin, M.E.

    2001-01-01

    Substantial progress has been made towards both understanding and control of internal transport barriers (ITBs) on DIII-D, resulting in the discovery of a new sustained high performance operating mode termed the Quiescent Double-Barrier (QDB) regime. The QDB regime combines core transport barriers with a quiescent, ELM-free H-mode edge (termed QH-mode), giving rise to separate (double) core and edge transport barriers. The core and edge barriers are mutually compatible and do not merge, resulting in broad core profiles with an edge pedestal. The QH-mode edge is characterized by ELM-free behavior with continuous multiharmonic MHD activity in the pedestal region, and has provided density and impurity control for 3.5 s (>20 τ E ) with divertor pumping. QDB plasmas are long-pulse high-performance candidates, having maintained a β N H 89 product of 7 for 5 energy confinement times (T i ≤16 keV, β N ≤2.9, H 89 ≤2.4, τ E ≤150 ms, DD neutron rate S n ≤4x10 15 s -1 ). The QDB regime has only been obtained in counter-NBI discharges (injection anti-parallel to plasma current) with divertor pumping. Other results include successful expansion of the ITB radius using (separately) both impurity injection and counter-NBI, and the formation of ITBs in the electron thermal channel using both ECH and strong negative central shear (NCS) at high power. These results are interpreted within a theoretical framework in which turbulence suppression is the key to ITB formation and control, and a decrease in core turbulence is observed in all cases of ITB formation. (author)

  6. Gamma Radiation to Increase Efficiency of Bacillus thuringiensis Thai Strain for Insect Pets Control

    International Nuclear Information System (INIS)

    Chanpaisaeng, Jariya; Keawsompong, Suttipun; Piadang, Nattaya; Tephan, Prakai; Keawchingduang, Wannapa

    2006-09-01

    Bacillus thuringiensis (Bt) isolates JCPT16 and JCPT68 were gamma-irradiated at 2, 4, 6 and 8 kGy. The efficiency of these Bt isolates on S. litura control was also undertaken. It was found that the 4 kGy irradiated JCPT16 isolate had lowest LC 50 of 6.6x10 3 spore/ml while the non-irradiated JCPT 16 isolate had LC 50 of 6.2x10 3 spore/ml. Whereas the irradiated JCPT68 isolate at 8 kGy was noticed to have the lowest LC 50 of 2.7 x 10 3 spores/ml, the non-irradiated JCPT68 had LC 50 of 1.8x10 3 spores/ml. The efficiency test of B. thuringiensis isolate on S. exigua showed that the 2 kGy irradiated JCPT16 isolate had the lowest LC 50 of 2.52x10 4 spores/ml while the non-irradiated JCPT16 isolate had LC 50 of 6.04x10 3 spores/ml. The irradiated JCPT68 isolate at 4 kGy had the lowest LC 50 of 5.41x10 4 spores/ml, the non irradiated JCPT68 had LC 50 of 1.51x10 4 spores/ml. According to LC 50 values, there were no significant differences of efficiency on S. litura and S. exigua control among Bt isolates irradiated at various concentrations. The isolate JCPT16, JCPT35, JCPT50 and JCPT68 irradiated at dose of 10 kGy showed higher UV tolerance. After expose by UV ray, most of irradiated isolates still displayed high efficiency of controlling S. litura, S. exigua and Plutella xylostell.

  7. Solar combisystems with forecast control to increase the solar fraction and lower the auxiliary energy cost

    DEFF Research Database (Denmark)

    Perers, Bengt; Furbo, Simon; Fan, Jianhua

    2011-01-01

    Solar Combi systems still need quite a lot of auxiliary energy especially in small systems without seasonal storage possibilities. The control of the auxiliary energy input both in time and power is important to utilize as much as possible of the solar energy available from the collectors and also...... energy sources. It can be either direct electric heating elements or a heat pump upgrading ambient energy in the air, ground, solar collector or waste heat from the house. The paper describes system modeling and simulation results. Advanced laboratory experiments are also starting now with three...

  8. Design measures to increase safety and reliability of power station control and protection systems

    International Nuclear Information System (INIS)

    Edelmann, J.; Spieth, W.

    1977-06-01

    The paper reviews a few criteria which exert a considerable influence on the safety and reliability of monitoring and control systems. When judging the safety and reliability of a system, it is of importance not only to look at the failures of just one part of a system but also to take into account the effect these failures have on the overall process. In this respect there is a marked difference between a centralized and a decentralized system. With the technical equipment nowadays at our disposal a high safety standard has been reached. Redundant and dynamic protection systems make the occurrence of a dangerous failure hypothetic. (Author)

  9. Analysis of the Fanconi anaemia complementation group A gene in acute myeloid leukaemia.

    Science.gov (United States)

    Condie, Alison; Powles, Raymond L; Hudson, Chantelle D; Shepherd, Valerie; Bevan, Stephen; Yuille, Martin R; Houlston, Richard S

    2002-09-01

    Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults. Around 10-15% of individuals with recessively inherited Fanconi anaemia (FA) develop AML. FA is one of a group of recessive syndromes characterized by excessive spontaneous chromosomal breakage in which heterozygote carriers appear to display an increased risk of cancer and there is some indirect evidence that FA carriers may also be at increased risk of AML. This suggests that FA genes may play a role in the development of AML in the wider context. To examine this proposition, further, we have screened samples from 79 AML patients for mutations in the major FA gene, FANCA. No truncating FANCA mutations were detected. One missense mutation previously designated as pathogenic and five novel missense mutations causing non-conservative amino acid substitutions were detected. The data suggests that while FANCA mutations are rare, FANCA mutations may contribute to the development of the disease in a subset of AML.

  10. Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia

    International Nuclear Information System (INIS)

    Tao, Yan-Fang; Fang, Fang; Hu, Shao-Yan; Lu, Jun; Cao, Lan; Zhao, Wen-Li; Xiao, Pei-Fang; Li, Zhi-Heng; Wang, Na-Na; Xu, Li-Xiao; Du, Xiao-Juan; Sun, Li-Chao; Li, Yan-Hong; Li, Yi-Ping; Xu, Yun-Yun; Ni, Jian; Wang, Jian; Feng, Xing; Pan, Jian

    2015-01-01

    Acute myeloid leukemia (AML) is the second-most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature of AML. GATA4 has been suggested to be a tumor suppressor gene regulated by promoter hypermethylation in various types of human cancers although the expression and promoter methylation of GATA4 in pediatric AML is still unclear. Transcriptional expression levels of GATA4 were evaluated by semi-quantitative and real-time PCR. Methylation status was investigated by methylation-specific PCR (MSP) and bisulfate genomic sequencing (BGS). The prognostic significance of GATA4 expression and promoter methylation was assessed in 105 cases of Chinese pediatric acute myeloid leukemia patients with clinical follow-up records. MSP and BGS analysis showed that the GATA4 gene promoter is hypermethylated in AML cells, such as the HL-60 and MV4-11 human myeloid leukemia cell lines. 5-Aza treatment significantly upregulated GATA4 expression in HL-60 and MV4-11 cells. Aberrant methylation of GATA4 was observed in 15.0 % (3/20) of the normal bone marrow control samples compared to 56.2 % (59/105) of the pediatric AML samples. GATA4 transcript levels were significantly decreased in AML patients (33.06 ± 70.94; P = 0.011) compared to normal bone marrow/idiopathic thrombocytopenic purpura controls (116.76 ± 105.39). GATA4 promoter methylation was correlated with patient leukocyte counts (WBC, white blood cells) (P = 0.035) and minimal residual disease MRD (P = 0.031). Kaplan-Meier survival analysis revealed significantly shorter overall survival time in patients with GATA4 promoter methylation (P = 0.014). Epigenetic inactivation of GATA4 by promoter hypermethylation was observed in both AML cell lines and pediatric AML samples; our study implicates GATA4 as a putative tumor suppressor gene in pediatric AML. In addition, our findings imply that GATA4 promoter methylation is correlated with WBC and MRD. Kaplan-Meier survival analysis

  11. A randomized controlled trial to increase information, motivation, and behavioral skills in Ugandan adolescents

    Science.gov (United States)

    Ybarra, Michele L.; Korchmaros, Josephine D.; Prescott, Tonya L.; Birungi, Ruth

    2015-01-01

    Background One in twenty-five Ugandan adolescents is HIV positive. Purpose Examine the impact of an Internet-based HIV prevention program on Information-Motivation-Behavior Skills Model-related constructs. Methods Three hundred and sixty-six sexually experienced and inexperienced students 12-18+ years-old in Mbarara, Uganda were randomly assigned to: the five-lesson CyberSenga program or treatment-as-usual. Half of the intervention participants were further randomized to a booster session. Assessments were collected at three and six months post-baseline. Results Participants’ HIV-related information improved over time at a greater rate for the intervention groups compared to the control group. Motivation for condom use changed to a greater degree over time for the intervention group – especially those in the intervention+booster group - compared to the control group. Behavioral skills for condom use, and motivation and behavioral skills for abstinence were statistically similar over time for both groups. Conclusions CyberSenga improves HIV preventive information and motivation to use condoms. PMID:25633626

  12. Result of randomized control trial to increase breast health awareness among young females in Malaysia.

    Science.gov (United States)

    Akhtari-Zavare, Mehrnoosh; Juni, Muhamad Hanafiah; Said, Salmiah Md; Ismail, Irmi Zarina; Latiff, Latiffah A; Ataollahi Eshkoor, Sima

    2016-08-08

    Breast cancer is the most common cancer and the second principal cause of cancer deaths in women worldwide as well as in Malaysia. Breast self-examination (BSE) has a role in raising breast cancer awareness among women and educational programs play an important role in breast cancer preventive behavior. The aim of this study is to develop, implement and evaluate the effectiveness of Breast Health Awareness program based on health belief model on knowledge of breast cancer and breast-selfexamination and BSE practice among female students in Malaysia. A single-blind randomized controlled trial was carried out among 370 female undergraduate students from January 2011 to April 2012 in two selected public universities in Malaysia. Participants were randomized to either the intervention group or the control group. The educational program was delivered to the intervention group. The outcome measures were assessed at baseline, 6, and 12 months after implementing the health educational program. Chi-square, independent samples t-test and two-way repeated measures ANOVA (GLM) were conducted in the course of the data analyses. Mean scores of knowledge on breast cancer (pMalaysia. The ANZCTR clinical trial registry ( ACTRN12616000831482 ), retrospectively registered on Jun 23, 2016 in ANZCTR.org.au.

  13. UV-screening chitosan nanocontainers: increasing the photostability of encapsulated materials and controlled release

    International Nuclear Information System (INIS)

    Anumansirikul, Nattaporm; Wittayasuporn, Mayura; Klinubol, Patcharawalai; Tachaprutinun, A; Wanichwecharungruang, Supason P

    2008-01-01

    Methyl ether terminated poly(ethylene glycol)-4-methoxycinnamoylphthaloylchitosan (PCPLC), a UV absorptive polymer, and methyl ether terminated poly(ethylene glycol)-phthaloylchitosan (PPLC) were synthesized, characterized and self-assembled into stable water-dispersible spherical nanoparticles. The encapsulation of a model compound, 2-ethylhexyl-4-methoxycinnamate (EHMC), was carried out to give particles with 67% (w/w) EHMC loading. The E to Z photoisomerization of EHMC encapsulated inside both particles was monitored and compared to non-encapsulated EHMC. Minimal E to Z photoisomerization was observed when EHMC was encapsulated in PCPLC particles prepared from a polymer with a maximum degree of 4-methoxycinnamoyl substitution. The results indicated that the grafted UVB absorptive chromophore, 4-methoxycinnamoyl moieties, situated at the shell of PCPLC nanoparticles acted as a UV-filtering barrier, protecting the encapsulated EHMC from the UVB radiation, thus minimizing its photoisomerization. In vitro experiments revealed the pH-dependent controlled release of EHMC from PCPLC and PPLC particles. Ex vivo experiments, using a Franz diffusion cell with baby mouse skin, indicated that neither PPLC nor PCPLC particles could penetrate the skin into the receptor medium after a 24 h topical application. When applied on the baby mouse skin, both EHMC-encapsulated PPLC and EHMC-encapsulated PCPLC showed comparable controlled releases of the EHMC. The released EHMC could transdermally penetrate the baby mouse skin

  14. UV-screening chitosan nanocontainers: increasing the photostability of encapsulated materials and controlled release

    Science.gov (United States)

    Anumansirikul, Nattaporm; Wittayasuporn, Mayura; Klinubol, Patcharawalai; Tachaprutinun, A.; Wanichwecharungruang, Supason P.

    2008-05-01

    Methyl ether terminated poly(ethylene glycol)-4-methoxycinnamoylphthaloylchitosan (PCPLC), a UV absorptive polymer, and methyl ether terminated poly(ethylene glycol)-phthaloylchitosan (PPLC) were synthesized, characterized and self-assembled into stable water-dispersible spherical nanoparticles. The encapsulation of a model compound, 2-ethylhexyl-4-methoxycinnamate (EHMC), was carried out to give particles with 67% (w/w) EHMC loading. The E to Z photoisomerization of EHMC encapsulated inside both particles was monitored and compared to non-encapsulated EHMC. Minimal E to Z photoisomerization was observed when EHMC was encapsulated in PCPLC particles prepared from a polymer with a maximum degree of 4-methoxycinnamoyl substitution. The results indicated that the grafted UVB absorptive chromophore, 4-methoxycinnamoyl moieties, situated at the shell of PCPLC nanoparticles acted as a UV-filtering barrier, protecting the encapsulated EHMC from the UVB radiation, thus minimizing its photoisomerization. In vitro experiments revealed the pH-dependent controlled release of EHMC from PCPLC and PPLC particles. Ex vivo experiments, using a Franz diffusion cell with baby mouse skin, indicated that neither PPLC nor PCPLC particles could penetrate the skin into the receptor medium after a 24 h topical application. When applied on the baby mouse skin, both EHMC-encapsulated PPLC and EHMC-encapsulated PCPLC showed comparable controlled releases of the EHMC. The released EHMC could transdermally penetrate the baby mouse skin.

  15. Increased Gamma Brainwave Amplitude Compared to Control in Three Different Meditation Traditions.

    Directory of Open Access Journals (Sweden)

    Claire Braboszcz

    Full Text Available Despite decades of research, effects of different types of meditation on electroencephalographic (EEG activity are still being defined. We compared practitioners of three different meditation traditions (Vipassana, Himalayan Yoga and Isha Shoonya with a control group during a meditative and instructed mind-wandering (IMW block. All meditators showed higher parieto-occipital 60-110 Hz gamma amplitude than control subjects as a trait effect observed during meditation and when considering meditation and IMW periods together. Moreover, this gamma power was positively correlated with participants meditation experience. Independent component analysis was used to show that gamma activity did not originate in eye or muscle artifacts. In addition, we observed higher 7-11 Hz alpha activity in the Vipassana group compared to all the other groups during both meditation and instructed mind wandering and lower 10-11 Hz activity in the Himalayan yoga group during meditation only. We showed that meditation practice is correlated to changes in the EEG gamma frequency range that are common to a variety of meditation practices.

  16. Climatic changes: what if the global increase of CO2 emissions cannot be kept under control?

    Directory of Open Access Journals (Sweden)

    L.A. Barreto de Castro

    Full Text Available Climatic changes threaten the planet. Most articles related to the subject present estimates of the disasters expected to occur, but few have proposed ways to deal with the impending menaces. One such threat is the global warming caused by the continuous increase in CO2 emissions leading to rising ocean levels due to the increasing temperatures of the polar regions. This threat is assumed to eventually cause the death of hundreds of millions of people. We propose to desalinize ocean water as a means to reduce the rise of ocean levels and to use this water for populations that need good quality potable water, precisely in the poorest regions of the planet. Technology is available in many countries to provide desalinated water at a justifiable cost considering the lives threatened both in coastal and desertified areas.

  17. Increasing viscosity and inertia using a robotically-controlled pen improves handwriting in children

    Science.gov (United States)

    Ben-Pazi, Hilla; Ishihara, Abraham; Kukke, Sahana; Sanger, Terence D

    2010-01-01

    The aim of this study was to determine the effect of mechanical properties of the pen on the quality of handwriting in children. Twenty two school aged children, ages 8–14 years wrote in cursive using a pen attached to a robot. The robot was programmed to increase the effective weight (inertia) and stiffness (viscosity) of the pen. Speed, frequency, variability, and quality of the two handwriting samples were compared. Increased inertia and viscosity improved handwriting quality in 85% of children (pHandwriting quality did not correlate with changes in speed, suggesting that improvement was not due to reduced speed. Measures of movement variability remained unchanged, suggesting that improvement was not due to mechanical smoothing of pen movement by the robot. Since improvement was not explained by reduced speed or mechanical smoothing, we conclude that children alter handwriting movements in response to pen mechanics. Altered movement could be caused by changes in proprioceptive sensory feedback. PMID:19794098

  18. Climate control of decadal-scale increases in apparent ages of eogenetic karst spring water

    Science.gov (United States)

    Martin, Jonathan B.; Kurz, Marie J.; Khadka, Mitra B.

    2016-09-01

    Water quantity and quality in karst aquifers may depend on decadal-scale variations in recharge or withdrawal, which we hypothesize could be assessed through time-series measurements of apparent ages of spring water. We tested this hypothesis with analyses of various age tracers (3H/3He, SF6, CFC-11, CFC-12, CFC-113) and selected solute concentrations [dissolved oxygen (DO), NO3, Mg, and SO4] from 6 springs in a single spring complex (Ichetucknee springs) in northern Florida over a 16-yr period. These springs fall into two groups that reflect shallow short (Group 1) and deep long (Group 2) flow paths. Some tracer concentrations are altered, with CFC-12 and CFC-113 concentrations yielding the most robust apparent ages. These tracers show a 10-20-yr monotonic increase in apparent age from 1997 to 2013, including the flood recession that followed Tropical Storm Debby in mid-2012. This increase in age indicates most water discharged during the study period recharged the aquifer within a few years of 1973 for Group 2 springs and 1980 for Group 1 springs. Inverse correlations between apparent age and DO and NO3 concentrations reflect reduced redox state in older water. Positive correlations between apparent age and Mg and SO4 concentrations reflect increased water-rock reactions. Concentrated recharge in the decade around 1975 resulted from nearly 2 m of rain in excess of the monthly average that fell between 1960 and 2014, followed by a nearly 4 m deficit to 2014. This excess rain coincided with two major El Niño events during the maximum cool phase in the Atlantic Multidecadal Oscillation. Although regional water withdrawal increased nearly 5-fold between 1980 and 2005, withdrawals represent only 2-5% of Ichetucknee River flow and are less important than decadal-long variations in precipitation. These results suggest that groundwater management should consider climate cycles as predictive tools for future water resources.

  19. Heparin-induced increase in serum levels of aminotranferases. A controlled clinical trial.

    Science.gov (United States)

    Nielsen, H K; Husted, S E; Koopmann, H D; Fasting, H; Simonsen, O; Andersen, K; Husegaard, H C; Petersen, T K

    1984-01-01

    Sixty-four patients over the age of 40 years, undergoing elective surgery of at least one hour's duration, were randomized to treatment with either a thromboembolic deterrent ( TED ) stocking (Kendall Co.) or subcutaneous low-dose heparin 5 000 IU every 12 hours. Serum levels of alanine aminotransferase (S-ALAT), aspartate aminotransferase (S-ASAT), gamma-glutamyl transpeptidase (S-gamma-GT) and alkaline phosphatase (S-ALP) were measured. S-ALAT increased significantly on the 5th and 10th postoperative day, from 27 +/- 2 (x +/- SE) to 40 +/- 4 (p less than 0.01) and 55 +/- 7 U/l (p less than 0.001), respectively, in the heparin group and was significantly higher in the heparin than in the TED group both on the 5th (p less than 0.01) and 10th (p less than 0.05) postoperative day. S-ASAT and S-gamma-GT increased significantly during heparin treatment, but did not differ significantly from the values of the TED group. No change in S-ALP was registered in either group. It is concluded that prophylactic treatment with low-dose heparin induces a significant increase in S-aminotransferase levels, especially in S-ALAT. The phenomenon has profound differential diagnostic implications in conditions such as pulmonary embolism and acute myocardial infarction.

  20. IL-7 treatment augments and prolongs sepsis-induced expansion of IL-10-producing B lymphocytes and myeloid-derived suppressor cells.

    Science.gov (United States)

    Kulkarni, Upasana; Herrmenau, Christoph; Win, Stephanie J; Bauer, Michael; Kamradt, Thomas

    2018-01-01

    Immunological dysregulation in sepsis is associated with often lethal secondary infections. Loss of effector cells and an expansion of immunoregulatory cell populations both contribute to sepsis-induced immunosuppression. The extent and duration of this immunosuppression are unknown. Interleukin 7 (IL-7) is important for the maintenance of lymphocytes and can accelerate the reconstitution of effector lymphocytes in sepsis. How IL-7 influences immunosuppressive cell populations is unknown. We have used the mouse model of peritoneal contamination and infection (PCI) to investigate the expansion of immunoregulatory cells as long-term sequelae of sepsis with or without IL-7 treatment. We analysed the frequencies and numbers of regulatory T cells (Tregs), double negative T cells, IL-10 producing B cells and myeloid-derived suppressor cells (MDSCs) for 3.5 months after sepsis induction. Sepsis induced an increase in IL-10+ B cells, which was enhanced and prolonged by IL-7 treatment. An increased frequency of MDSCs in the spleen was still detectable 3.5 months after sepsis induction and this was more pronounced in IL-7-treated mice. MDSCs from septic mice were more potent at suppressing T cell proliferation than MDSCs from control mice. Our data reveal that sepsis induces a long lasting increase in IL-10+ B cells and MDSCs. Late-onset IL-7 treatment augments this increase, which should be relevant for clinical interventions.

  1. NWTC Researchers Field-Test Advanced Control Turbine Systems to Increase Performance, Decrease Structural Loading of Wind Turbines and Plants

    Energy Technology Data Exchange (ETDEWEB)

    2015-08-01

    Researchers at the National Renewable Energy Laboratory's (NREL's) National Wind Technology Center (NWTC) are studying component controls, including new advanced actuators and sensors, for both conventional turbines as well as wind plants. This research will help develop innovative control strategies that reduce aerodynamic structural loads and improve performance. Structural loads can cause damage that increase maintenance costs and shorten the life of a turbine or wind plant.

  2. Mildly disabled persons with multiple sclerosis use similar net joint power strategies as healthy controls when walking speed increases.

    Science.gov (United States)

    Brincks, John; Christensen, Lars Ejsing; Rehnquist, Mette Voigt; Petersen, Jesper; Sørensen, Henrik; Dalgas, Ulrik

    2018-01-01

    To improve walking in persons with multiple sclerosis (MS), it is essential to understand the underlying mechanisms of walking. This study examined strategies in net joint power generated or absorbed by hip flexors, hip extensors, hip abductors, knee extensors, and plantar flexors in mildly disabled persons with MS and healthy controls at different walking speeds. Thirteen persons with MS and thirteen healthy controls participated and peak net joint power was calculated using 3D motion analysis. In general, no differences were found between speed-matched healthy controls and persons with MS, but the fastest walking speed was significantly higher in healthy controls (2.42 m/s vs. 1.70 m/s). The net joint power increased in hip flexors, hip extensors, hip abductors, knee extensors and plantar flexors in both groups, when walking speed increased. Significant correlations between changes in walking speed and changes in net joint power of plantar flexors, hip extensors and hip flexors existed in healthy controls and persons with MS, and in net knee extensor absorption power of persons with MS only. In contrast to previous studies, these findings suggest that mildly disabled persons with MS used similar kinetic strategies as healthy controls to increase walking speed.

  3. Increasing LIGO sensitivity by feedforward subtraction of auxiliary length control noise

    International Nuclear Information System (INIS)

    Meadors, Grant David; Riles, Keith; Kawabe, Keita

    2014-01-01

    LIGO, the Laser Interferometer Gravitational-wave Observatory, has been designed and constructed to measure gravitational wave strain via differential arm length. The LIGO 4 km Michelson arms with Fabry–Perot cavities have auxiliary length control servos for suppressing Michelson motion of the beam-splitter and arm cavity input mirrors, which degrades interferometer sensitivity. We demonstrate how a post facto pipeline improves a data sample from LIGO Science Run 6 with feedforward subtraction. Dividing data into 1024 s windows, we numerically fit filter functions representing the frequency-domain transfer functions from Michelson length channels into the gravitational-wave strain data channel for each window, then subtract the filtered Michelson channel noise (witness) from the strain channel (target). In this paper we describe the algorithm, assess achievable improvements in sensitivity to astrophysical sources, and consider relevance to future interferometry. (paper)

  4. Improving Code Quality of the Compact Muon Solenoid Electromagnetic Calorimeter Control Software to Increase System Maintainability

    CERN Multimedia

    Holme, Oliver; Dissertori, Günther; Djambazov, Lubomir; Lustermann, Werner; Zelepoukine, Serguei

    2013-01-01

    The Detector Control System (DCS) software of the Electromagnetic Calorimeter (ECAL) of the Compact Muon Solenoid (CMS) experiment at CERN is designed primarily to enable safe and efficient operation of the detector during Large Hadron Collider (LHC) data-taking periods. Through a manual analysis of the code and the adoption of ConQAT [1], a software quality assessment toolkit, the CMS ECAL DCS team has made significant progress in reducing complexity and improving code quality, with observable results in terms of a reduction in the effort dedicated to software maintenance. This paper explains the methodology followed, including the motivation to adopt ConQAT, the specific details of how this toolkit was used and the outcomes that have been achieved. [1] ConQAT, Continuous Quality Assessment Toolkit; https://www.conqat.org/

  5. Covariate adjustments in randomized controlled trials increased study power and reduced biasedness of effect size estimation.

    Science.gov (United States)

    Lee, Paul H

    2016-08-01

    This study aims to show that under several assumptions, in randomized controlled trials (RCTs), unadjusted, crude analysis will underestimate the Cohen's d effect size of the treatment, and an unbiased estimate of effect size can be obtained only by adjusting for all predictors of the outcome. Four simulations were performed to examine the effects of adjustment on the estimated effect size of the treatment and power of the analysis. In addition, we analyzed data from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study (older adults aged 65-94), an RCT with three treatment arms and one control arm. We showed that (1) the number of unadjusted covariates was associated with the effect size of the treatment; (2) the biasedness of effect size estimation was minimized if all covariates were adjusted for; (3) the power of the statistical analysis slightly decreased with the number of adjusted noise variables; and (4) exhaustively searching the covariates and noise variables adjusted for can lead to exaggeration of the true effect size. Analysis of the ACTIVE study data showed that the effect sizes adjusting for covariates of all three treatments were 7.39-24.70% larger than their unadjusted counterparts, whereas the effect size would be elevated by at most 57.92% by exhaustively searching the variables adjusted for. All covariates of the outcome in RCTs should be adjusted for, and if the effect of a particular variable on the outcome is unknown, adjustment will do more good than harm. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. An Increase in Dietary Supplement Exposures Reported to US Poison Control Centers.

    Science.gov (United States)

    Rao, Nisha; Spiller, Henry A; Hodges, Nichole L; Chounthirath, Thiphalak; Casavant, Marcel J; Kamboj, Amrit K; Smith, Gary A

    2017-09-01

    The objective of this study was to investigate the epidemiology of dietary supplement exposures in the USA. A retrospective analysis was conducted of out-of-hospital dietary supplement exposures reported to the National Poison Data System from 2000 through 2012. There were 274,998 dietary supplement exposures from 2000 through 2012. The annual rate of dietary supplement exposures per 100,000 population increased by 46.1% during 2000-2002, decreased 8.8% during 2002-2005, and then increased again by 49.3% from 2005 to 2012. These trends were influenced by the decrease in ma huang exposures starting in 2002. Miscellaneous dietary supplements accounted for 43.9% of all exposures, followed by botanicals (31.9%), hormonal products (15.1%), and other supplements (5.1%). The majority of dietary supplement exposures (70.0%) occurred among children younger than 6 years old and were acute (94.0%) and unintentional (82.9%). Serious medical outcomes accounted for 4.5% of exposures and most (95.0%) occurred among individuals 6 years and older. Ma huang products, yohimbe, and energy products were the categories associated with the greatest toxicity. There was an overall increase in the rate of dietary supplement exposures from 2000 through 2012. Although the majority of these exposures did not require treatment at a health care facility or result in serious medical outcomes, exposures to yohimbe and energy products were associated with considerable toxicity. Our results demonstrate the success of the FDA ban on ma huang products and the need for FDA regulation of yohimbe and energy products in the USA.

  7. Control of microstructure to increase the tolerance of zirconium alloys to hydride cracking

    International Nuclear Information System (INIS)

    Coleman, C.E.; Sagat, S.; Amouzouvi, K.F.

    1987-12-01

    The microstructure of Zr-2.5 Nb has been altered in three ways in attempts to increase the alloy's tolerance to delayed hydride cracking, namely by breaking up the β-phase which reduces diffusivity of hydrogen and decreases crack velocity, by means of a gettering element (yttrium) which reduces susceptibility to cracking although the yttrium alloy has low toughness and poor corrosion resistance, and by reducing the number of basal plane normals in the main stressing direction which improves resistance to crack growth

  8. IKKα Promotes Intestinal Tumorigenesis by Limiting Recruitment of M1-like Polarized Myeloid Cells

    Directory of Open Access Journals (Sweden)

    Serkan I. Göktuna

    2014-06-01

    Full Text Available The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC therapy.

  9. Azacitidine and lenalidomide as an alternative treatment for refractory acute myeloid leukemia: a case report

    Directory of Open Access Journals (Sweden)

    Juliana Todaro

    Full Text Available CONTEXT:Refractory acute myeloid leukemia (AML is a difficult disease to control with second or third-line chemotherapy regimens. In this report, we describe using azacitidine in combination with lenalidomide as salvage therapy.CASE REPORT:52-year-old female was diagnosed with refractory AML and high-risk cytogenetics: complex monosomal karyotype consisting of t (3, 3 in association with monosomy 7 and del 5q. Morphological remission associated with maintenance of the cytogenetic abnormality of chromosome 3 and disappearance of the abnormalities relating to chromosomes 5 and 7 was achieved after three cycles of combination therapy with azacitidine and lenalidomide.CONCLUSION:Azacitidine plus lenalidomide can be a therapeutic option for patients with refractory AML, as illustrated in this case.

  10. Azacitidine and lenalidomide as an alternative treatment for refractory acute myeloid leukemia: a case report.

    Science.gov (United States)

    Todaro, Juliana; Bollmann, Patrícia Weinschenker; Rother, Edna Terezinha; del Giglio, Auro

    2015-01-01

    Refractory acute myeloid leukemia (AML) is a difficult disease to control with second or third-line chemotherapy regimens. In this report, we describe using azacitidine in combination with lenalidomide as salvage therapy. 52-year-old female was diagnosed with refractory AML and high-risk cytogenetics: complex monosomal karyotype consisting of t (3, 3) in association with monosomy 7 and del 5q. Morphological remission associated with maintenance of the cytogenetic abnormality of chromosome 3 and disappearance of the abnormalities relating to chromosomes 5 and 7 was achieved after three cycles of combination therapy with azacitidine and lenalidomide. Azacitidine plus lenalidomide can be a therapeutic option for patients with refractory AML, as illustrated in this case.

  11. Fish oil-supplementation increases appetite in healthy adults. A randomized controlled cross-over trial.

    Science.gov (United States)

    Damsbo-Svendsen, Signe; Rønsholdt, Mia Dybkjær; Lauritzen, Lotte

    2013-07-01

    Marine n-3 fatty acids are hypothesized to have beneficial effects on obesity and cancer cachexia possibly via an effect on appetite. The aim of this study was to investigate, if fish oil-supplementation affects appetite in healthy individuals. In a randomized cross-over study, 20 normal-weight subjects (50% females) were given ten 0.5-mL capsules/day of fish oil or soybean oil for 3 weeks separated by 1-week wash-out. In the end of each period, appetite was assessed by 10-cm visual analog scales immediately before and after a standardized breakfast. Results were analyzed in accordance with the paired design considering oil sequence and gender. All subjects completed both periods with a compliance of 96% and oil sequence did not affect the results. There was no difference between the two supplements in any pre-breakfast appetite scores, but the post-prandial sensation of being full was 1.21 cm (0.20; 2.22) lower after the fish oil-period. Furthermore, there was a supplement × gender-interaction on "desire to eat more" due to a score increase of 1.09 cm (0.28; 1.90) in women only. These results suggest that marine n-3 fatty acid may increase appetite. This finding would be potentially beneficial for patients with compromised nutritional status. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors

    Science.gov (United States)

    Park, Tea Soon; Huo, Jeffrey S.; Peters, Ann; Talbot, C. Conover; Verma, Karan; Zimmerlin, Ludovic; Kaplan, Ian M.; Zambidis, Elias T.

    2012-01-01

    Nonviral conversion of skin or blood cells into clinically useful human induced pluripotent stem cells (hiPSC) occurs in only rare fractions (∼0.001%–0.5%) of donor cells transfected with non-integrating reprogramming factors. Pluripotency induction of developmentally immature stem-progenitors is generally more efficient than differentiated somatic cell targets. However, the nature of augmented progenitor reprogramming remains obscure, and its potential has not been fully explored for improving the extremely slow pace of non-integrated reprogramming. Here, we report highly optimized four-factor reprogramming of lineage-committed cord blood (CB) myeloid progenitors with bulk efficiencies of ∼50% in purified episome-expressing cells. Lineage-committed CD33+CD45+CD34− myeloid cells and not primitive hematopoietic stem-progenitors were the main targets of a rapid and nearly complete non-integrated reprogramming. The efficient conversion of mature myeloid populations into NANOG+TRA-1-81+ hiPSC was mediated by synergies between hematopoietic growth factor (GF), stromal activation signals, and episomal Yamanaka factor expression. Using a modular bioinformatics approach, we demonstrated that efficient myeloid reprogramming correlated not to increased proliferation or endogenous Core factor expressions, but to poised expression of GF-activated transcriptional circuits that commonly regulate plasticity in both hematopoietic progenitors and embryonic stem cells (ESC). Factor-driven conversion of myeloid progenitors to a high-fidelity pluripotent state was further accelerated by soluble and contact-dependent stromal signals that included an implied and unexpected role for Toll receptor-NFκB signaling. These data provide a paradigm for understanding the augmented reprogramming capacity of somatic progenitors, and reveal that efficient induced pluripotency in other cell types may also require extrinsic activation of a molecular framework that commonly regulates self

  13. Increased Urinary Phthalate Levels in Women with Uterine Leiomyoma: A Case-Control Study.

    Science.gov (United States)

    Kim, Young Ah; Kho, Younglim; Chun, Kyoung Chul; Koh, Jae Whoan; Park, Jeong Woo; Bunderson-Schelvan, Melisa; Cho, Yoon Hee

    2016-12-15

    We assessed the urinary concentrat