Description: The life cycle of dust in the interstellar medium is heavily influenced by outflows from asymptotic giant branch (AGB) and red supergiant (RSG) stars, a large fraction of which is contributed by a few very dusty sources. We compute the dust input to the Small Magellanic Cloud (SMC) by fitting the multi-epoch mid-infrared spectral energy distributions of AGB/RSG candidates with models from the Grid of RSG and AGB ModelS grid, allowing us to estimate the luminosities and dust-production rates (DPRs) of the entire population. By removing contaminants, we guarantee a high-quality data set with reliable DPRs and a complete inventory of the dustiest sources. We find a global AGB/RSG dust-injection rate of (1.3 ± 0.1) x 10 –6 M  yr –1 , in agreement with estimates derived from mid-infrared colours and excess fluxes. As in the Large Magellanic Cloud, a majority (66 per cent) of the dust arises from the extreme AGB stars, which comprise only 7 per cent of our sample. A handful of far-infrared sources, whose 24 μm fluxes exceed their 8 μm fluxes, dominate the dust input. Their inclusion boosts the global DPR by 1.5 x , making it necessary to determine whether they are AGB stars. Model assumptions, rather than missing data, are the major sources of uncertainty; depending on the choice of dust shell expansion speed and dust optical constants, the global DPR can be up to 10 times higher. Our results suggest a non-stellar origin for the SMC dust, barring as yet undiscovered evolved stars with very high DPRs.

Description: The stars in the Magellanic Clouds with the largest degree of obscuration are used to probe the highly uncertain physics of stars in the asymptotic giant branch (AGB) phase of evolution. Carbon stars in particular provide key information on the amount of third dredge-up and mass-loss. We use two independent stellar evolution codes to test how a different treatment of the physics affects the evolution on the AGB. The output from the two codes is used to determine the rates of dust formation in the circumstellar envelope, where the method used to determine the dust is the same for each case. The stars with the largest degree of obscuration in the Large Magellanic Cloud (LMC) and Small Magellanic Cloud (SMC) are identified as the progeny of objects of initial mass 2.5–3 M and ~1.5 M , respectively. This difference in mass is motivated by the difference in the star formation histories of the two galaxies, and offers a simple explanation of the redder infrared colours of C-stars in the LMC compared to their counterparts in the SMC. The comparison with the Spitzer colours of C-rich AGB stars in the SMC shows that a minimum surface carbon mass fraction X ( C ) ~ 5  x  10 –3 must have been reached by stars of initial mass around 1.5 M . Our results confirm the necessity of adopting low-temperature opacities in stellar evolutionary models of AGB stars. These opacities allow the stars to obtain mass-loss rates high enough (10 –4 M yr –1 ) to produce the amount of dust needed to reproduce the Spitzer colours.

Description: We report the first infrared study of the low-energy (〈20 eV) electron-induced reactions of condensed methanol. Our goal is to simulate processes which occur when high-energy cosmic rays interact with interstellar and cometary ices, where methanol, a precursor of several prebiotic species, is relatively abundant. The interactions of high-energy radiation, such as cosmic rays ( E max  ~ 10 20  eV), with matter produce large numbers of low-energy secondary electrons, which are known to initiate radiolysis reactions in the condensed phase. Using temperature programmed desorption (TPD) and infrared reflection absorption spectroscopy (IRAS), we have investigated low-energy (5–20 eV) and high-energy (~1000 eV) electron-induced reactions in condensed methanol (CH 3 OH). IRAS has the benefit that it does not require thermal processing prior to product detection. Using IRAS, we have found evidence for the formation of ethylene glycol (HOCH 2 CH 2 OH), formaldehyde (CH 2 O), dimethyl ether (CH 3 OCH 3 ), methane (CH 4 ), carbon dioxide (CO 2 ), carbon monoxide (CO), and the hydroxyl methyl radical ( · CH 2 OH) upon both low-energy and high-energy electron irradiation of condensed methanol at ~85 K. Additionally, TPD results, presented herein, are similar for methanol films irradiated with both 1000 eV and 20 eV electrons. These IRAS and TPD findings are qualitatively consistent with the hypothesis that high-energy condensed phase radiolysis is mediated by low-energy electron-induced reactions. Moreover, methoxymethanol (CH 3 OCH 2 OH) could serve as a tracer molecule for electron-induced reactions in the interstellar medium. The results of experiments such as ours may provide a fundamental understanding of how complex organic molecules are synthesized in cosmic ices.

Description: Coxiella burnetii replicates within permissive host cells by employing a Dot/Icm type IV secretion system (T4SS) to translocate effector proteins that direct the formation of a parasitophorous vacuole. C57BL/6 mouse macrophages restrict the intracellular replication of the C. burnetii Nine Mile phase II (NMII) strain. However, eliminating Toll-like receptor 2 (TLR2) permits bacterial replication, indicating that the restriction of bacterial replication is immune mediated. Here, we examined whether additional innate immune pathways are employed by C57BL/6 macrophages to sense and restrict NMII replication. In addition to the known role of TLR2 in detecting and restricting NMII infection, we found that TLR4 also contributes to cytokine responses but is not required to restrict bacterial replication. Furthermore, the TLR signaling adaptors MyD88 and Trif are required for cytokine responses and restricting bacterial replication. The C. burnetii NMII T4SS translocates bacterial products into C57BL/6 macrophages. However, there was little evidence of cytosolic immune sensing of NMII, as there was a lack of inflammasome activation, T4SS-dependent cytokine responses, and robust type I interferon (IFN) production, and these pathways were not required to restrict bacterial replication. Instead, endogenous tumor necrosis factor (TNF) produced upon TLR sensing of C. burnetii NMII was required to control bacterial replication. Therefore, our findings indicate a primary role for TNF produced upon immune detection of C. burnetii NMII by TLRs, rather than cytosolic PRRs, in enabling C57BL/6 macrophages to restrict bacterial replication.

Description: Using the PACS and SPIRE spectrometers on-board the Herschel Space Observatory , we obtained spectra of two red supergiants (RSGs) in the Large Magellanic Cloud (LMC). Multiple rotational CO emission lines ( J  = 6–5 to 15-14) and 15 H 2 O lines were detected from IRAS 05280–6910, and one CO line was detected from WOH G64. This is the first time that CO rotational lines have been detected from evolved stars in the LMC. Their CO line intensities are as strong as those of the Galactic RSG, VY CMa. Modelling the CO lines and the spectral energy distribution results in an estimated mass-loss rate for IRAS 05280–6910 of 3  x  10 –4  M  yr –1 . The model assumes a gas-to-dust ratio and a CO-to-H 2 abundance ratio is estimated from the Galactic values scaled by the LMC metallicity ([Fe/H] ~ –0.3), i.e. that the CO-to-dust ratio is constant for Galactic and LMC metallicities within the uncertainties of the model. The key factor determining the CO line intensities and the mass-loss rate found to be the stellar luminosity.

Description: Background The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. Methods The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. Results One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Conclusions Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). Clinical trials number ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

Description: Genetic reference panels are widely used to map complex, quantitative traits in model organisms. We have generated new high-resolution genetic maps of 259 mouse inbred strains from recombinant inbred strain panels (C57BL/6J x DBA/2J, ILS/IbgTejJ x ISS/IbgTejJ, and C57BL/6J x A/J) and chromosome substitution strain panels (C57BL/6J-Chr#〈A/J〉, C57BL/6J-Chr#〈PWD/Ph〉, and C57BL/6J-Chr#〈MSM/Ms〉). We genotyped all samples using the Affymetrix Mouse Diversity Array with an average intermarker spacing of 4.3 kb. The new genetic maps provide increased precision in the localization of recombination breakpoints compared to the previous maps. Although the strains were presumed to be fully inbred, we found residual heterozygosity in 40% of individual mice from five of the six panels. We also identified de novo deletions and duplications, in homozygous or heterozygous state, ranging in size from 21 kb to 8.4 Mb. Almost two-thirds (46 out of 76) of these deletions overlap exons of protein coding genes and may have phenotypic consequences. Twenty-nine putative gene conversions were identified in the chromosome substitution strains. We find that gene conversions are more likely to occur in regions where the homologous chromosomes are more similar. The raw genotyping data and genetic maps of these strain panels are available at http://churchill-lab.jax.org/website/MDA .

Description: Purpose: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Patients and Methods: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN). Results: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders ( N = 62) had 2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( N = 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 x 10 6 /kg; patients 〉50 kg: 0.1 to 2.5 x 10 8 CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response. Conclusions: Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.

Description: Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer British Journal of Cancer 112, 1340 (14 April 2015). doi:10.1038/bjc.2015.74 Authors: K L Mahon, H-M Lin, L Castillo, B Y Lee, M Lee-Ng, M D Chatfield, K Chiam, S N Breit, D A Brown, M P Molloy, G M Marx, N Pavlakis, M J Boyer, M R Stockler, R J Daly, S M Henshall & L G Horvath