A population of gamma-ray emitting globular clusters seen with the Fermi Large Area Telescope

Globular clusters with their large populations of millisecond pulsars (MSPs) are believed to be potential emitters of high-energy gamma-ray emission. Our goal is to constrain the millisecond pulsar populations in globular clusters from analysis of gamma-ray observations. We use 546 days of continuous sky-survey observations obtained with the Large Area Telescope aboard the Fermi Gamma-ray Space Telescope to study the gamma-ray emission towards 13 globular clusters. Steady point-like high-energy gamma-ray emission has been significantly detected towards 8 globular clusters. Five of them (47 Tucanae, Omega Cen, NGC 6388, Terzan 5, and M 28) show hard spectral power indices $(0.7 < \Gamma <1.4)$ and clear evidence for an exponential cut-off in the range 1.0-2.6 GeV, which is the characteristic signature of magnetospheric emission from MSPs. Three of them (M 62, NGC 6440 and NGC 6652) also show hard spectral indices $(1.0 < \Gamma < 1.7)$, however the presence of an exponential cut-off can not be unambiguously established. Three of them (Omega Cen, NGC 6388, NGC 6652) have no known radio or X-ray MSPs yet still exhibit MSP spectral properties. From the observed gamma-ray luminosities, we estimate the total number of MSPs that is expected to be present in these globular clusters. We show that our estimates of the MSP population correlate with the stellar encounter rate and we estimate 2600-4700 MSPs in Galactic globular clusters, commensurate with previous estimates. The observation of high-energy gamma-ray emission from a globular cluster thus provides a reliable independent method to assess their millisecond pulsar populations that can be used to make constraints on the original neutron star X-ray binary population, essential for understanding the importance of binary systems in slowing the inevitable core collapse of globular clusters.Comment: Accepted for publication in A&A. Corresponding authors: J. Kn\"odlseder, N. Webb, B. Pancraz

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies

Background: In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation. Methods: We describe here the design and implementation of a customized genome-wide genotyping array, the ‘TxArray’, comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios. Results: We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms. Conclusions: We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0211-x) contains supplementary material, which is available to authorized users

Safety and antitumor activity of pembrolizumab in advanced programmed death Ligand 1-positive endometrial cancer: Results from the KEYNOTE-028 study

Endometrial cancer (EC) identified at an early stage is successfully treated in a majority of patients with surgery with or without radiotherapy or chemotherapy. For patients with advanced disease, however, the prognosis is poor; 5-year survival rates are less than 50% in patients with lymph node metastases and less than 20% in those with peritoneal or distant metastases. Novel, more effective therapies are needed for patients with advanced or recurrent EC. Immune approaches are promising. The interaction of programmed death ligand 1 (PD-L1) with programmed death 1 (PD-1)-an immune checkpoint receptor expressed on tumor-infiltrating T cells-can lead to their functional inactivation and prevent tumor immune evasion. Targeted immune therapy directed against PD-1 or PD-L1 can result in objective tumor responses in a wide spectrum of cancers and could play a major role in treatment of EC. A positive correlation between tumor PD-L1 expression and clinical activity against a number of tumors using PD-1 pathway blockade was the rationale for assessing the safety and efficacy of a PD-1-blocking antibody, pembrolizumab, in 20 advanced, PD-L1positive solid tumor cohorts in the KEYNOTE-028 (NCT02054806) trial. The investigators report results from the EC cohort in this article. Eligible patients had locally advanced or metastatic PD-L1-positive EC progressing after standard therapy were eligible. Pembrolizumab 10 mg/kg was administered intravenously every 2 weeks up to 24 months or until disease progression or intolerable toxicity. The primary study efficacy end point was objective response rate by RECIST (Response Evaluation Criteria In Solid Tumors, version 1.1). Secondary end points assessed included safety, duration of response (DOR), progression-free survival, and overall survival. The data cutoff for this analysis was February 17, 2016. Seventy-five patients with advanced EC were screened for PD-L1 expression; 36 of these (48.0%) had PD-L1-positive tumors, and 24 (32.0%) were enrolled. Among these 24 patients, 15 (62.5%) had received at least 2 previous lines of therapy for advanced disease; 3 of these patients (13.0%) achieved confirmed partial response (95% confidence interval, 2.8%-33.6%); median DOR was not reached. At time of data cutoff, 2 patients were still receiving treatment and an ongoing response. An additional 2 patients (13.0%) achieved stable disease; median duration was 24.6 weeks. A partial response was achieved in 1 patient who had a polymerase E mutation. Treatment-related adverse effects (AEs) occurred in 13 patients (54.2%); more than 10% of patients experienced fatigue (n = 5; 20.8%), pruritus (n = 4; 16.7%), pyrexia (n = 3; 12.5%), and decreased appetite (n = 3; 12.5%). Only 4 patients (16.7%) experienced grade 3 treatment-related AEs. There were no grade 4 AEs or immune-mediated AEs or treatment discontinuation because of an AE. These data show that pembrolizumab has a favorable safety profile and durable antitumor activity in patients with heavily pretreated advanced PD-L1-positive EC. The safety and efficacy of pembrolizumab and the utility of biomarkers including PD-L1 in a cohort of patients with EC are being investigated in the phase 2 multicohort KEYNOTE-158 trial