53,902 research outputs found
Retinoic acid sensitizes acute myeloid leukemia cells to ER stress
No full textAcute myeloid leukemia (AML) is caused by the blockade of hematopoietic myeloid precursors at different stages of differentiation. A subtype of AML, acute promyelocytic leukemia (APL), is a paradigm of differentiation therapy since retinoic acid (RA) is able to induce leukemic blast terminal differentiation leading to cure rates exceeding 80% when administered in combination with chemotherapy. Although APL patients refractory to RA or who relapsed are very effectively treated with arsenic trioxide (ATO) in combination with RA, the elevated costs limit its use in developing countries and in first line therapy so that RA plus chemotherapy currently remain the standard of care (1, 2). Most importantly non-APL acute myeloid leukemia do not respond to RA indicating the need for novel strategies to sensitize AML cells to RA. Here we show that RA-triggered differentiation of APL cells induces endoplasmic reticulum (ER) stress slightly activating the unfolded protein response (UPR). This is sufficient to render leukemic cell lines and human primary blasts very sensitive to doses of ER stress inducing drugs, like tunicamycin (Tm), that are not toxic for the same cells in the absence of RA or for most cell types. Furthermore we observed that low doses of Tm, even in the absence of RA, are sufficient to strongly increase ATO toxicity. Indeed both RA-sensitive and RA-resistant APL cell lines resulted sensitive to Tm-ATO combined treatment at low doses of ATO that are ineffective in the absence of ER stress. The use of inhibitors targeting specific UPR branches indicate that the Protein Kinase RNA-like Endoplasmic Reticulum kinase (PERK) pathway protects differentiating APL cells from ER stress rendering it an interesting therapeutic molecular target. Finally, we extended our observations in a non-APL model, assessing that RA sensitize the non-APL cell line HL60 to ER stress. Altogether our data indicate ER stress as a possible target for designing novel combination therapeutic strategies in AML
Use of arsenic trioxide in secondary acute promyelocytic leukemia developing after treatment of multiple sclerosis with mitoxantrone
No full text1ST MEASUREMENT OF GAMMA(D(S)(+)-]MU+NU)/GAMMA(D(S)(+)-]PHI-PI+)
No full textComplete Author List:
ACOSTA D, ATHANAS M, MASEK G, PAAR H, BEAN A, GRONBERG J, KUTSCHKE R, MENARY S, MORRISON RJ, NAKANISHI S, NELSON HN, NELSON TK, RICHMAN JD, RYD A, TAJIMA H, SCHMIDT D, SPERKA D, WITHERELL MS, PROCARIO M, YANG S, BALEST R, CHO K, DAOUDI M, FORD WT, JOHNSON DR, LINGEL K, LOHNER M, RANKIN P, SMITH JG, ALEXANDER JP, BEBEK C, BERKELMAN K, BESSON D, BROWDER TE, CASSEL DG, CHO HA, COFFMAN DM, DRELL PS, EHRLICH R, GALIK RS, GARCIASCIVERES M, GEISER B, GITTELMAN B, GRAY SW, HARTILL DL, HELTSLEY BK, JONES CD, JONES SL, KANDASWAMY J, KATAYAMA N, KIM PC, KREINICK DL, LUDWIG GS, MASUI J, MEVISSEN J, MISTRY NB, NG CR, NORDBERG E, OGG M, PATTERSON JR, PETERSON D, RILEY D, SALMAN S, SAPPER M, WORDEN H, WURTHWEIN F, AVERY P, FREYBERGER A, RODRIGUEZ J, STEPHENS R, YELTON J, CINABRO D, HENDERSON S, KINOSHITA K, LIU T, SAULNIER M, SHEN F, WILSON R, YAMAMOTO H, ONG B, SELEN M, SADOFF AJ, AMMAR R, BALL S, BARINGER P, COPPAGE D, COPTY N, DAVIS R, HANCOCK N, KELLY M, KWAK N, LAM H, KUBOTA Y, LATTERY M, NELSON JK, PATTON S, PERTICONE D, POLING R, SAVINOV V, SCHRENK S, WANG R, ALAM MS, KIM IJ, NEMATI B, ONEILL JJ, SEVERINI H, SUN CR, ZOELLER MM, CRAWFORD G, DAUBENMIER CM, FULTON R, FUJINO D, GAN KK, HONSCHEID K, KAGAN H, KASS R, LEE J, MALCHOW R, MORROW F, SKOVPEN Y, SUNG M, WHITE C, WHITMORE J, WILSON P, BUTLER F, FU X, KALBFLEISCH G, LAMBRECHT M, ROSS WR, SKUBIC P, SNOW J, WANG PL, WOOD M, BORTOLETTO D, BROWN DN, FAST J, MCILWAIN RL, MIAO T, MILLER DH, MODESITT M, SCHAFFNER SF, SHIBATA EI, SHIPSEY IPJ, WANG PN, BATTLE M, ERNST J, KROHA H, ROBERTS S, SPARKS K, THORNDIKE EH, WANG CH, DOMINICK J, SANGHERA S, SHELKOV V, SKWARNICKI T, STROYNOWSKI R, VOLOBOUEV I, ZADOROZHNY P, ARTUSO M, HE D, GOLDBERG M, HORWITZ N, KENNETT R, MONETI GC, MUHEIM F, MUKHIN Y, PLAYFER S, ROZEN Y, STONE S, THULASIDAS M, VASSEUR G, ZHU G, BARTELT J, CSORNA SE, EGYED Z, JAIN V, SHELDON P, AKERIB DS, BARISH B, CHADHA M, CHAN S, COWEN DF, EIGEN G, MILLER JS, OGRADY C, URHEIM J, WEINSTEIN A
Molecular monitoring of hematologic malignancies: current and future issues
No full textGenetic markers associated with hematologic malignancies such as acute promyelocytic leukemia (APL) can be detected with high sensitivity and specificity using the reverse-transcription polymerase chain reaction (RT-PCR). This procedure can be applied to monitor minimal residual disease. In patients with APL, RT-PCR is now being used to detect molecular relapse, and a strong association has been found between outcome and the treatment of molecular as opposed to hematologic relapse. In APL, results from PCR assays are also being used to guide therapy. Prognostic groups can be defined using molecular and clinical characteristics of the disease as well as patient characteristics. In the future, PCR monitoring strategies may be adapted to the risk of relapse of individual patients. Patients at high risk of relapse may be monitored much more rigorously than patients at low risk of relapse. Although RT-PCR is in routine use as a clinical tool, the lack of standardization of techniques in different laboratories has resulted in some difficulties in interpretation of results. There is a real need for an international consensus on standardization of PCR techniques
A 2 h periodic variation in the low-mass X-ray binary Ser X-1
No full textSpectroscopy of the low-mass X-ray binary Ser X-1 using the Gran Telescopio Canarias have revealed a ?2 h periodic variability that is present in the three strongest emission lines. We tentatively interpret this variability as due to orbital motion, making it the first indication of the orbital period of Ser X-1. Together with the fact that the emission lines are remarkably narrow, but still resolved, we show that a main-sequence K dwarf together with a canonical 1.4 M? neutron star gives a good description of the system. In this scenario, the most likely place for the emission lines to arise is the accretion disc, instead of a localized region in the binary (such as the irradiated surface or the stream-impact point), and their narrowness is due instead to the low inclination (?10°) of Ser X-1
Exclusive and inclusive semileptonic decays of B mesons to D mesons
No full textcomplete author list: Fulton R.; Jensen T.; Johnson D.; Kagan H.; Kass R.; Morrow F.; Whitmore J.; Wilson P.; Bortoletto D.; Chen W.; Dominick J.; McIlwain R.; Miller D.; Ng C.; Schaffner S.; Shibata E.; Shipsey I.; Yao W.; Battle M.; Sparks K.; Thorndike E.; Wang C.; Alam M.; Kim I.; Li W.; Romero V.; Sun C.; Wang P.; Zoeller M.; Goldberg M.; Haupt T.; Horwitz N.; Jain V.; Mestayer M.; Moneti G.; Rozen Y.; Rubin P.; Sharma V.; Skwarnicki T.; Thulasidas M.; Zhu G.; Csorna S.; Letson T.; Alexander J.; Artuso M.; Bebek C.; Berkelman K.; Browder T.; Cassel D.; Cheu E.; Coffman D.; Crawford G.; Dewire J.; Drell P.; Ehrlich R.; Galik R.; Garcia-Sciveres M.; Geiser B.; Gittelman B.; Gray S.; Halling A.; Hartill D.; Heltsley B.; Honscheid K.; Kandaswamy J.; Katayama N.; Kreinick D.; Lewis J.; Ludwig G.; Masui J.; Mevissen J.; Mistry N.; Nandi S.; Nordberg E.; O'Grady C.; Peterson D.; Pisharody M.; Riley D.; Sapper M.; Selen M.; Silverman A.; Stone S.; Worden H.; Worris M.; Sadoff A.; Avery P.; Besson D.; Garren L.; Yelton J.; Kinoshita K.; Pipkin F.; Procario M.; Wilson R.; Wolinski J.; Xiao D.; Zhu Y.; Ammar R.; Baringer P.; Coppage D.; Davis R.; Haas P.; Kwak N.; Lam H.; Ro S.; Kubota Y.; Nelson J.; Perticone D.; Poling R.; Fulton R.; Poling R.; Perticone D.; Nelson J.; Fulton R.</p
Erosie door open taludbekledingen. Samenvattend verslag + Bijlage A t/m D
No full textOpen taludbekledingen die bestaan uit in verband geplaatste betonblokken met gaten, bieden de mogelijkheid vegetatie te doen groeien, waardoor mogelijk een milieuvriendelijke oever kan worden verkregen. In het pioniersstadium van de vegetatie is het evenwel ongewenst dat de gatvulling uitspoelt. Teneinde de relatie tussen waterbeweging en erosie van de gatvulling vast te stellen, is door de Dienst Weg- en Waterbouwkunde van Rijkswaterstaat per brief d.d. 16 maart 1987 (kenmerk WB 570), opdracht verleend aan het Waterloopkundig Laboratorium tot het uitvoeren van onderzoek naar de erosie door open taludbekledingen. Het doel van het onderzoek is het ontwikkelen van ontwerprichtlijnen voor taludbekledingen met gaten die groter zijn dan de zand- of filterkorrels eronder. Hiertoe dient de kritieke waterbeweging bij een oever- of dijkbekleding te worden vastgesteld, waarbij nog toelaatbare erosie is te verwachten. De toelaatbare erosie mag daarbij maximaal gelijk zijn aan de hoeveelheid sediment in de gaten. Filter- of basismateriaal gelegen onder de elementen mag dus niet uitspoelen. Bij oeverbekledingen waar vegetatie een rol moet gaan spelen, is de toelaatbare erosie kleiner, dat wil zeggen in de gaten dient sediment achter te blijven.Steenzettingen - TAW/EN
Measurement of the B̄→D*lν̄ branching fractions and -Vcb-
No full textcomplete author list:
Barish B.; Chadha M.; Chan S.; Cowen D.; Eigen G.; Miller J.; O'Grady C.; Urheim J.; Weinstein A.; Acosta D.; Athanas M.; Masek G.; Paar H.; Gronberg J.; Kutschke R.; Menary S.; Morrison R.; Nakanishi S.; Nelson H.; Nelson T.; Qiao C.; Richman J.; Ryd A.; Tajima H.; Sperka D.; Witherell M.; Procario M.; Balest R.; Cho K.; Daoudi M.; Ford W.; Johnson D.; Lingel K.; Lohner M.; Rankin P.; Smith J.; Alexander J.; Bebek C.; Berkelman K.; Bloom K.; Browder T.; Cassel D.; Cho H.; Coffman D.; Crowcroft D.; Drell P.; Ehrlich R.; Gaidarev P.; Galik R.; Garcia-Sciveres M.; Geiser B.; Gittelman B.; Gray S.; Hartill D.; Heltsley B.; Jones C.; Jones S.; Kandaswamy J.; Katayama N.; Kim P.; Kreinick D.; Ludwig G.; Masui J.; Mevissen J.; Mistry N.; Ng C.; Nordberg E.; Patterson J.; Peterson D.; Riley D.; Salman S.; Sapper M.; Würthwein F.; Avery P.; Freyberger A.; Rodriguez J.; Yang S.; Yelton J.; Cinabro D.; Henderson S.; Liu T.; Saulnier M.; Wilson R.; Yamamoto H.; Bergfeld T.; Eisenstein B.; Gollin G.; Ong B.; Palmer M.; Selen M.; Thaler J.; Edwards K.; Ogg M.; Bellerive A.; Britton D.; Hyatt E.; MacFarlane D.; Patel P.; Spaan B.; Sadoff A.; Ammar R.; Ball S.; Baringer P.; Bean A.; Besson D.; Coppage D.; Copty N.; Davis R.; Hancock N.; Kelly M.; Kotov S.; Kravchenko I.; Kwak N.; Lam H.; Kubota Y.; Lattery M.; Momayezi M.; Nelson J.; Patton S.; Perticone D.; Poling R.; Savinov V.; Schrenk S.; Wang R.; Alam M.; Kim I.; Nemati B.; Ling Z.; O'Neill J.; Severini H.; Sun C.; Wappler F.; Crawford G.; Daubenmier C.; Fulton R.; Fujino D.; Gan K.; Honscheid K.; Kagan H.; Kass R.; Lee J.; Malchow R.; Skovpen Y.; Sung M.; White C.; Zoeller M.; Butler F.; Fu X.; Kalbfleisch G.; Ross W.; Skubic P.; Wood M.; Fast J.; Mcilwain R.; Miao T.; Miller D.; Modesitt M.; Payne D.; Shibata E.; Shipsey I.; Wang P.; Battle M.; Ernst J.; Gibbons L.; Kwon Y.; Roberts S.; Thorndike E.; Wang C.; Dominick J.; Lambrecht M.; Sanghera S.; Shelkov V.; Skwarnicki T.; Stroynowski R.; Volobouev I.; Wei G.; Zadorozhny P.; Artuso M.; Goldberg M.; He D.; Horwitz N.; Kennett R.; Mountain R.; Moneti G.; Muheim F.; Mukhin Y.; Playfer S.; Rozen Y.; Stone S.; Thulasidas M.; Vasseur G.; Xing X.; Zhu G.; Bartelt J.; Csorna S.; Egyed Z.; Jain V.; Gibaut D.; Kinoshita K.; Kinoshita K.; Barish B
Measurement of the D+/- production asymmetry in 7 TeV pp collisions
No full textThe asymmetry in the production cross-section \sigma of D+/- mesons, A_P = (\sigma(D+) - \sigma(D-))/(\sigma(D+) + \sigma(D-)), is measured in bins of pseudorapidity \eta and transverse momentum p_T within the acceptance of the LHCb detector. The result is obtained with a sample of D+ -> K_S pi+ decays corresponding to an integrated luminosity of 1.0 fb^-1, collected in pp collisions at a centre of mass energy of 7 TeV at the Large Hadron Collider. When integrated over the kinematic range 2.0 K_S pi+ decay is negligible. No significant dependence on \eta or p_T is observed
Assessment of minimal residual disease (MRD) in CBFbeta/MYH11-positive acute myeloid leukemias by qualitative and quantitative RT-PCR amplification of fusion transcripts
No full textThe inv(16)(p13q22) chromosomal rearrangement associated with FAB M4Eo acute myeloid leukemia (AML) subtype is characterized by the presence of the CBFbeta/MYH11 fusion transcript that can be used to detect minimal residual disease (MRD). However, qualitative RT-PCR studies of MRD have so far produced conflicting results and seem of limited prognostic value. We have evaluated retrospectively MRD in a large series of CBFbeta/MYH11-positive patients employing both qualitative and quantitative (real-time PCR) approaches. 186 bone marrow samples from 36 patients were examined with a median follow-up of 27.5 months; 15 patients relapsed during follow-up. In qualitative studies, carried out by 'nested' RT-PCR assay, all patients in complete remission (CR) immediately after induction/consolidation therapy were found to be PCR positive. However, follow-up samples at later time points were persistently negative (except one case) in patients remaining in continuous CR (CCR) for more than 12 months. 16 patients were evaluated by quantitative real-time PCR assay: CBFbeta/MYH11 transcript copy number was normalized for expression of the housekeeping gene ABL, expressed as fusion gene copy number per 10(4) copies of ABL. A 2-3 log decline in leukemic transcript copy number was observed after induction/consolidation therapy. After achieving CR, the mean copy number was significantly higher in patients destined to relapse compared to patients remaining in CCR (151 vs 9, P < 0.0001 by Mann-Whitney test). Moreover, in CCR patients, the copy number dropped below the detection threshold after the treatment protocol was completed and remained undetectable in subsequent MRD analysis in accordance with results obtained by qualitative RT-PCR. On the contrary, in the seven patients who relapsed, the copy number in CR never declined below the detection threshold; thus a cut-off value discriminating these two groups of patients could be established. The findings of our study, if confirmed, might confer an important predictive value to quantitative real-time PCR determinations of MRD in patients with inv(16) leukemia
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