Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Forskningskortlægning og forskervurdering af skandinavisk forskning i året 2012 i institutioner for de 0-6-årige

Sammenfatning Hvad ønsker vi at få at vide? Arten og kvaliteten af skandinavisk forskning i året 2012 i dagtilbud for de 0-6-årige gen-nem en forskningskortlægning og forskervurdering. Hvem ønsker at vide det og hvorfor? Projektet er udført af Dansk Clearinghouse for Uddannelsesforskning som et samarbejds-projekt med Danmarks Evalueringsinstitut. Projektet støttes af Utdanningsdirektoratet i Norge og Skolverket i Sverige. EVA anvender resultatet af den gennemførte forskningskortlægning og -vurdering til ud-arbejdelse af årsrapporten Bakspejlet og som baggrundsdata i Nordic Base of Early Childhood Education and Care (NB-ECEC). Hvad fandt vi frem til? Først og fremmest blev det konstateret, at den øgede opmærksomhed på dagtilbud, som har kunnet iagttages gennem de senere år i de skandinaviske lande, nu er slået igennem også i forskningen i form af en kraftig forøgelse af forskningen regnet i antallet af pro-jekter. Forøgelsen i antallet af projekter er hovedsageligt forbundet med en øgning i antallet af undersøgelser fra Norge. Der blev i året Der blev i året 2012 publiceret 83 undersøgelser om dagtilbud for de 0-6-årige. Heraf havde 16 data fra Danmark, 47 fra Norge og 25 fra Sverige, mens fem udover skandinavi-ske data også havde data fra ikke-skandinaviske lande. 67 af undersøgelserne har god videnskabelig kvalitet. Det pædagogiske personale er undersøgelsesgenstand i 70 % af årets studier. I 48 % ind-går børnene. Forældre indgår i 9 % af undersøgelserne. Flertallet (84 %) af årets undersøgelser inddrager et bredere samfundsmæssigt perspek-tiv i undersøgelsens analyser. Et sådant perspektiv findes ikke i de resterende 16 % af undersøgelserne. 40 % af undersøgelserne anvender et etnografisk design, efterfulgt af tværsnitsstudier (25 %) og holdningsundersøgelser (17 %). I årets forskning er der 31 % af studierne, som anvender kvantitativ analyse. Feltets typiske forskning har et kvalitativt design. De 67 undersøgelser om institutioner for 0-6-årige i Skandinavien, udgivet i 2012 med tilfredsstillende forskningskvalitet, er inddelt efter fem prædefinerede temaer, som der er opmærksomhed på i praksis og policy på feltet. De valgte temaer berøres i 44 af de 67 undersøgelser. Temaerne er: De yngste børn • Sprogudvikling • Dagtilbuddets strukturelle og fysiske rammer som læringsmiljø • Udvikling af dagtilbud • Dagtilbuddets betydnin

2,7- and 4,9-Dialkynyldihydropyrene molecular switches : syntheses, properties, and charge transport in single-molecule junctions

This paper describes the syntheses of several functionalized dihydropyrene (DHP) molecular switches with different substitution patterns. Regioselective nucleophilic alkylation of a 5-substituted dimethyl isophthalate allowed the development of a workable synthetic protocol for the preparation of 2,7-alkyne-functionalized DHPs. Synthesis of DHPs with surface-anchoring groups in the 2,7- and 4,9-positions is described. The molecular structures of several intermediates and DHPs were elucidated by X-ray single-crystal diffraction. Molecular properties and switching capabilities of both types of DHPs were assessed by light irradiation experiments, spectroelectrochemistry, and cyclic voltammetry. Spectroelectrochemistry, in combination with density functional theory (DFT) calculations, shows reversible electrochemical switching from the DHP forms to the cyclophanediene (CPD) forms. Charge-transport behavior was assessed in single-molecule scanning tunneling microscope (STM) break junctions, combined with density functional theory-based quantum transport calculations. All DHPs with surface-contacting groups form stable molecular junctions. Experiments show that the molecular conductance depends on the substitution pattern of the DHP motif. The conductance was found to decrease with increasing applied bias

Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib

© 2016 Elsevier Masson SASBackground & aims The availability of non-tumorigenic and tumorigenic liver progenitor cell (LPC) lines affords a method to screen putative anti-liver cancer agents to identify those that are selectively effective. To prove this principle we tested thalidomide and a range of its derivatives and compared them to lenalidomide and sorafenib, to assess their growth-inhibitory effects. Methods Cell growth, the mitotic and apoptotic index of cell cultures were measured using the Cellavista instrument (SynenTec) using commercially available reagents. Results Neither lenalidomide nor thalidomide (100 µM) affected tumorigenic LPCs but killed their non-tumorigenic counterparts. Sorafenib arrested growth in both cell types. All but two derivatives of thalidomide were ineffective; of the two effective derivatives, one (thalidomide C1) specifically affected the tumorigenic cell line (10 µM). Mitotic and apoptotic analyses revealed that thalidomide C1 induced apoptotic cell death and not mitotic arrest. Conclusions This study shows that screens incorporating non-tumorigenic and tumorigenic liver cell lines are a sound approach to identify agents that are effective and selective. A high throughput instrument such as the Cellavista affords robust and reproducible objective measurements with a large number of replicates that are reliable. These experiments show that neither lenalidomide nor thalidomide are potentially useful for anti-liver cancer therapy as they kill non-tumorigenic liver cells and not their tumorigenic counterparts. Sorafenib in contrast, is highly effective, but not selective. One tested thalidomide derivative has potential as an anti-tumor drug since it induced growth arrest; and importantly, it selectively induced apoptotic cell death only in tumorigenic liver progenitor cells