Arabidopsis glucosinolates trigger a contrasting transcriptomic response in a generalist and a specialist herbivore.

Phytophagous insects have to deal with toxic defense compounds from their host plants. Although it is known that insects have evolved genes and mechanisms to detoxify plant allochemicals, how specialist and generalist precisely respond to specific secondary metabolites at the molecular level is less understood. Here we studied the larval performance and transcriptome of the generalist moth Heliothis virescens and the specialist butterfly Pieris brassicae feeding on Arabidopsis thaliana genotypes with different glucosinolate (GS) levels. H. virescens larvae gained significantly more weight on the GS-deficient mutant quadGS compared to wild-type (Col-0) plants. On the contrary, P. brassicae was unaffected by the presence of GS and performed equally well on both genotypes. Strikingly, there was a considerable differential gene expression in H. virescens larvae feeding on Col-0 compared to quadGS. In contrast, compared to H. virescens, P. brassicae displayed a much-reduced transcriptional activation when fed on both plant genotypes. Transcripts coding for putative detoxification enzymes were significantly upregulated in H. virescens, along with digestive enzymes and transposable elements. These data provide an unprecedented view on transcriptional changes that are specifically activated by GS and illustrate differential molecular responses that are linked to adaptation to diet in lepidopteran herbivores

Decay Process for Three - Species Reaction - Diffusion System

We propose the deterministic rate equation of three-species in the reaction - diffusion system. For this case, our purpose is to carry out the decay process in our three-species reaction-diffusion model of the form $A+B+C\to D$. The particle density and the global reaction rate are also shown analytically and numerically on a two-dimensional square lattice with the periodic boundary conditions. Especially, the crossover of the global reaction rate is discussed in both early-time and long-time regimes.Comment: 6 pages, 3 figures, Late

Synthesis of Fluorine-18 Functionalized Nanoparticles for use as in vivo Molecular Imaging Agents

Nanoparticles containing fluorine-18 were prepared from block copolymers made by ring opening metathesis polymerization (ROMP). Using the fast initiating ruthenium metathesis catalyst (H_2IMes)(pyr)_2(Cl)_2Ru=CHPh, low polydispersity amphiphilic block copolymers were prepared from a cinnamoyl-containing hydrophobic norbornene monomer and a mesyl-terminated PEG-containing hydrophilic norbornene monomer. Self-assembly into micelles and subsequent cross-linking of the micelle cores by light-activated dimerization of the cinnamoyl groups yielded stable nanoparticles. Incorporation of fluorine-18 was achieved by nucleophilic displacement of the mesylates by the radioactive fluoride ion with 31% incorporation of radioactivity. The resulting positron-emitting nanoparticles are to be used as in vivo molecular imaging agents for use in tumor imaging

The HADES Tracking System

The tracking system of the dielectron spectrometer HADES at GSI Darmstadt is formed out of 24 low-mass, trapezoidal multi-layer drift chambers providing in total about 30 square meter of active area. Low multiple scattering in the in total four planes of drift chambers before and after the magnetic field is ensured by using helium-based gas mixtures and aluminum cathode and field wires. First in-beam performance results are contrasted with expectations from simulations. Emphasis is placed on the energy loss information, exploring its relevance regarding track recognition.Comment: 6 pages, 4 figures, presented at the 10th Vienna Conference on Instrumentation, Vienna, February 2004, to be published in NIM A (special issue

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy

Background: The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm (P = 0.015). Methods: This post hoc analysis determines whether the clinical benefits of glasdegib are restricted to patients who achieve CR, or if they extend to those who do not achieve CR. Results: In patients who did not achieve CR, the addition of glasdegib to LDAC improved overall survival (OS) versus LDAC alone (hazard ratio = 0.63 [95% confidence interval, 0.41-0.98]; P = 0.0182; median OS, 5.0 vs 4.1 months). Additionally, more patients receiving glasdegib + LDAC achieved durable recovery of absolute neutrophil count (≥ 1000/μl, 45.6% vs 35.5%), hemoglobin (≥ 9 g/dl, 54.4% vs 38.7%), and platelets (≥ 100,000/μl, 29.8% vs 9.7%). Transfusion independence was achieved by 15.0% and 2.9% of patients receiving glasdegib + LDAC and LDAC alone, respectively. Conclusions: Collectively, these data suggest that there are clinical benefits with glasdegib in the absence of CR. Trial registration: ClinicalTrials.gov NCT01546038 (March 7, 2012

Low-Energy Proton Testing Using Cyclotrons Sources

No abstract availabl

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

Background: After discontinuing ruxolitinib, the outcome of patients with myelofibrosis reportedly has been poor. The authors investigated whether disease characteristics before the receipt of ruxolitinib may predict drug discontinuation in patients with myelofibrosis and whether reasons for drug discontinuation, disease phase at discontinuation, and salvage therapies may influence the outcome. Methods: A centralized electronic clinical database was created in 20 European hematology centers, including clinical and laboratory data for 524 patients who received ruxolitinib for myelofibrosis. Results: At 3\ua0years, 40.8% of patients had stopped ruxolitinib. Baseline predictors of drug discontinuation were: intermediate-2\u2013risk/high-risk category (Dynamic International Prognostic Score System), a platelet count <100 7109 per liter, transfusion dependency, and unfavorable karyotype. At last contact, 268 patients (51.1%) had discontinued therapy, and the median drug exposure was 17.5\ua0months. Fifty patients (18.7%) died while taking ruxolitinib. The reasons for discontinuation in the remaining 218 patients were the lack (22.9%) or loss (11.9%) of a spleen response, ruxolitinib-related adverse events (27.5%), progression to blast phase (23.4%), ruxolitinib-unrelated adverse events (9.2%), and allogeneic transplantation during response (5.1%). The median survival after ruxolitinib was 13.2\ua0months and was significantly better in the 167 patients who discontinued ruxolitinib in chronic phase (27.5 vs 3.9\ua0months for those who discontinued in blast phase; P\ua0<.001). No survival differences were observed among patients who discontinued ruxolitinib in chronic phase because of lack of response, loss of response, or ruxolitinib-related adverse events. The use of investigational agents and/or ruxolitinib rechallenge were associated with improved outcome. Conclusions: The survival of patients with myelofibrosis after discontinuation of ruxolitinib is poor, particularly for those who discontinue in blast phase. Salvage therapies can improve outcome, emphasizing the need for novel therapies

The High-Acceptance Dielectron Spectrometer HADES

HADES is a versatile magnetic spectrometer aimed at studying dielectron production in pion, proton and heavy-ion induced collisions. Its main features include a ring imaging gas Cherenkov detector for electron-hadron discrimination, a tracking system consisting of a set of 6 superconducting coils producing a toroidal field and drift chambers and a multiplicity and electron trigger array for additional electron-hadron discrimination and event characterization. A two-stage trigger system enhances events containing electrons. The physics program is focused on the investigation of hadron properties in nuclei and in the hot and dense hadronic matter. The detector system is characterized by an 85% azimuthal coverage over a polar angle interval from 18 to 85 degree, a single electron efficiency of 50% and a vector meson mass resolution of 2.5%. Identification of pions, kaons and protons is achieved combining time-of-flight and energy loss measurements over a large momentum range. This paper describes the main features and the performance of the detector system