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

Heme Oxygenase (HO-1) Rescue of Adipocyte Dysfunction in HO-2 Deficient Mice via Recruitment of Epoxyeicosatrienoic Acids (EETs) and Adiponectin

Background/Aims: HO-1 and EETs are functionally linked and their interactions influence body weight, insulin sensitivity, and serum levels of inflammatory cytokines in metabolic syndrome phenotype of HO-2 null mice. The HO-2 isozyme is essential for regulating physiological levels of ROS. Recent studies have suggested a potential role of EET in modifying adipocyte differentiation through up-regulation of HO-1-adiponectin-AkT signaling in human mesenchymal stem cells (MSCs). Our aim was to examine the consequences of HO deficiency on MSC-derived adipogenesis in vitro using MSC derived from HO-2 null and WT mice in vivo. Methods: Four-month-old HO-2 null (HO-2-/-) and B6/129SF2/J (WT) mice were divided into three groups (four mice/group): WT, HO-2-/-, and HO-2-/- +CoPP. Adipogenesis was performed on purified MSC-derived adipocytes cultured in adipogenic differentiation media and an EET-agonist was added every 3 days. Results: HO-2 depletion of MSC adipocytes resulted in increased adipogenesis (p\u3c0.01) and increased levels of inflammatory cytokines including (TNF)-alpha (p\u3c0.05), (MCP)-1 (p\u3c0.05), and (IL-1)-beta (p\u3c0.05). These results were accompanied by decreases in HO-1 (p\u3c0.05) and subsequently EET and HO activity (p\u3c0.05). Up-regulation of HO-1 resulted in decreased MSC-derived adipocyte differentiation, decreased production of TNF-alpha and MCP-1 and increased levels of adiponectin (p\u3c0.05). Cyp2J5 (p\u3c0.05), HO-1 (p\u3c0.05), and adiponectin mRNA levels (p\u3c0.05) were also decreased in visceral adipose tissue isolated from HO-2 null compared to WT mice. EET agonist stimulation of MSC adipocytes derived from HO-2 null mice yielded similar results. Conclusion: Increased levels of EET and HO-1 are essential for protection against the adverse effects of adipocyte hypertrophy and the ensuing metabolic syndrome. These results offer a portal into therapeutic approaches for the prevention of the metabolic syndrome

Search for doubly charged Higgs bosons in like-sign dilepton final states at root s=7 TeV with the ATLAS detector

A search for doubly charged Higgs bosons decaying to pairs of electrons and/or muons is presented. The search is performed using a data sample corresponding to an integrated luminosity of 4.7 fb(-1) of pp collisions at root s = 7 TeV collected by the ATLAS detector at the LHC. Pairs of prompt, isolated, high-p(T) leptons with the same electric charge (e(+/-)e(+/-), e(+/-)mu, mu(+/-)mu(+/-)) are selected, and their invariant mass distribution is searched for a narrow resonance. No significant excess over Standard Model background expectations is observed, and limits are placed on the cross section times branching ratio for pair production of doubly charged Higgs bosons. The masses of doubly charged Higgs bosons are constrained depending on the branching ratio into these leptonic final states. Assuming pair production, coupling to left-handed fermions, and a branching ratio of 100% for each final state, masses below 409 GeV, 375 GeV, and 398 GeV are excluded for e(+/-)e(+/-), e(+/-)mu(+/-),and mu(+/-)mu(+/-), respectively