The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer

Programmed death 1 (PD-1) is a co-inhibitory receptor in the CD28/CTL-4 family, and functions as a negative regulator of the immune system. Tumor-infiltrating lymphocytes (TIL) in many epithelial cancers express PD-1, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway, and promising results from two recent clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 confirm the clinical relevance of this pathway in human cancer. To explore the role of PD-1+ TIL in human breast cancer, we performed immunohistochemistry studies on a tissue microarray encompassing 660 breast cancer cases with detailed clinical annotation and outcomes data. PD-1+ TIL were present in 104 (15.8%) of the 660 breast cancer cases. Their presence was associated with tumor size, grade, and lymph node status, and was differentially associated with the intrinsic subtypes of breast cancer. In univariate survival analyses, the presence of PD-1+ TIL was associated with a significantly worse overall survival (HR=2.736, p<0.001). In subset analyses, the presence of PD-1+ TIL was associated with significantly worse overall survival in the luminal B HER2− subtype (HR=2.678, p<0.001), the luminal B HER2+ subtype (HR=3.689, p<0.001), and the basal-like subtype (HR=3.140, p<0.001). This is the first study to demonstrate that the presence of PD-1+ TIL is associated with poor prognosis in human breast cancer, with important implications for the potential application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this diseas

PTP1B expression is an independent positive prognostic factor in human breast cancer

Protein tyrosine phosphatase 1B (PTP1B) is a non-transmembrane protein tyrosine phosphatase that has come into focus as a critical regulator of multiple signaling pathways. The role of PTP1B in breast cancer remains unclear with evidence suggesting that PTP1B can exert both tumor-suppressing and tumor-promoting effects. To better define the role of PTP1B in human breast cancer, and its relationship with HER2, we performed immunohistochemical studies on a large cohort of functionally annotated primary breast cancer specimens. 683 of 1,402 (49%) evaluable primary breast cancers are positive for PTP1B. There is no statistically significant association between PTP1B expression and age, tumor size, T stage, histologic grade, lymph node status, or histological subtype. Of note, there is no significant association between PTP1B expression and HER2 expression (PTP1B expression53.1% in HER2+ cancers vs. 47.5% in HER2− cancers, p=0.0985). However, PTP1B expression is significantly associated with estrogen receptor expression (PTP1B expression50.7% in ER+ cancers vs. 43.1% in ER− cancers, p=0.0137) and intrinsic molecular subtype (PTP1B expression53.9% in the luminal B HER2+ subtype and 37.9% in the basal-like subtype). Of note, multivariate analyses demonstrate that PTP1B is an independent predictor of improved survival in breast cancer (HR 0.779, p=0.006). Taken together, we demonstrate in the largest study to date that (1) PTP1B is commonly expressed in breast cancer, (2) there is no association or functional impact of PTP1B expression in HER2+ breast cancer, and (3) PTP1B expression in breast cancer is associated with significantly improved clinical outcome. Until additional studies are performed, caution should be exercised in using PTP1B inhibitors in human breast cance

Ormosil-coated conjugated polymers for the detection of explosives in aqueous environments

This project has received funding from the TIRAMISU project, funded by the European Commission’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 284747, and the Engineering and Physical Sciences Research Council under grants EP/K503940/1, EP/K503162/1, EP/N509759/1. IDWS acknowledges a Royal Society Wolfson Research Merit Award. The research data supporting this publication can be accessed at http://dx.doi.org/10.17630/3875a099-bb75-4ae1-82e5-0b98b6b7ebc6.A fluorescence-based sensor for detecting explosives, based on a conjugated polymer coated with an ormosil layer, has been developed for use in aqueous environments. The conjugated polymer Super Yellow was spin-coated onto glass substrates prior to a further spin-coating of an MTEOS/TFP-TMOS-based ormosil film, giving an inexpensive, solution-based barrier material for ruggedization of the polymer to an aqueous environment. The sensors showed good sensitivity to 2,4-DNT in the aqueous phase at micromolar and millimolar concentrations, and also showed good recovery of fluorescence when the explosive was removed.PostprintPeer reviewe

Preconcentration techniques for trace explosive sensing

This project has received funding from NATO Science for Peace & Security under grant agreement MYP G5355, the European Union’s Seventh Framework Programme for research, technological development and demonstration under agreement no 284747, and the EPSRC under EP/K503940/1.Trace sensing of explosive vapours is a method in humanitarian demining and Improvised Explosives Device (IED) detection that has received increasing attention recently, since accurate, fast, and reliable chemical detection is highly important for threat identification. However, trace molecule sampling in the field can be extremely difficult due to factors including weather, locale, and very low vapour pressure of the explosive. Preconcentration of target molecules onto a substrate can provide a method to collect higher amounts of analyte for analysis. We used the commercial fluoropolymer Aflas as a preconcentrator material to sorb explosive molecules to the surface, allowing subsequent detection of the explosives via the luminescence quenching response from the organic polymer Super Yellow. The preconcentration effect of Aflas was confirmed and characterised with 2,4-DNT, prior to field sampling being conducted at a test minefield in Croatia by placing preconcentration strips in the entrance of the hives, where honeybees have collected explosive materials during free-flying. In this work we show for the first time a method for confirmation of landmines combining honeybee colonies containing a preconcentration material and subsequent monitoring of luminescence quenching.PostprintPeer reviewe

Investigation of altering single-nucleotide polymorphism density on the power to detect trait loci and frequency of false positive in nonparametric linkage analyses of qualitative traits

Genome-wide linkage analysis using microsatellite markers has been successful in the identification of numerous Mendelian and complex disease loci. The recent availability of high-density single-nucleotide polymorphism (SNP) maps provides a potentially more powerful option. Using the simulated and Collaborative Study on the Genetics of Alcoholism (COGA) datasets from the Genetics Analysis Workshop 14 (GAW14), we examined how altering the density of SNP marker sets impacted the overall information content, the power to detect trait loci, and the number of false positive results. For the simulated data we used SNP maps with density of 0.3 cM, 1 cM, 2 cM, and 3 cM. For the COGA data we combined the marker sets from Illumina and Affymetrix to create a map with average density of 0.25 cM and then, using a sub-sample of these markers, created maps with density of 0.3 cM, 0.6 cM, 1 cM, 2 cM, and 3 cM. For each marker set, multipoint linkage analysis using MERLIN was performed for both dominant and recessive traits derived from marker loci. Our results showed that information content increased with increased map density. For the homogeneous, completely penetrant traits we created, there was only a modest difference in ability to detect trait loci. Additionally, as map density increased there was only a slight increase in the number of false positive results when there was linkage disequilibrium (LD) between markers. The presence of LD between markers may have led to an increased number of false positive regions but no clear relationship between regions of high LD and locations of false positive linkage signals was observed

Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer

Recent studies in multiple epithelial cancers have shown thatthe inhibitory receptor programmed cell death 1 (PD-1) is expressed on tumor-infiltrating lymphocytes and/or programmed death ligand 1 (PD-L1) is expressed on tumor cells, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway. In addition, phase 1 clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 have shown promising results in several human cancers. The purpose of this study was to investigate the impact of PD-L1 expression in human breast cancer specimens. We conducted an immunohistochemistry study using a tissue microarray encompassing 650 evaluable formalin-fixed breast cancer cases with detailed clinical annotation and outcomes data. PD-L1 was expressed in 152 (23.4%) of the 650 breast cancer specimens. Expression was significantly associated with age, tumor size, AJCC primary tumor classification, tumor grade, lymph node status, absence of ER expression, and high Ki-67 expression. In univariate analysis, PD-L1 expression was associated with a significantly worse OS. In multivariate analysis, PD-L1 expression remained an independent negative prognostic factor for OS. In subset analyses, expression of PD-L1 was associated with significantly worse OS in the luminal B HER2− subtype, the luminal B HER2+ subtype, the HER2 subtype, and the basal-like subtype. This is the first study to demonstrate that PD-L1 expression is an independent negative prognostic factor in human breast cancer. This finding has important implications for the application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease

Gamma-ray Observations Under Bright Moonlight with VERITAS

Imaging atmospheric Cherenkov telescopes (IACTs) are equipped with sensitive photomultiplier tube (PMT) cameras. Exposure to high levels of background illumination degrades the efficiency of and potentially destroys these photo-detectors over time, so IACTs cannot be operated in the same configuration in the presence of bright moonlight as under dark skies. Since September 2012, observations have been carried out with the VERITAS IACTs under bright moonlight (defined as about three times the night-sky-background (NSB) of a dark extragalactic field, typically occurring when Moon illumination > 35%) in two observing modes, firstly by reducing the voltage applied to the PMTs and, secondly, with the addition of ultra-violet (UV) bandpass filters to the cameras. This has allowed observations at up to about 30 times previous NSB levels (around 80% Moon illumination), resulting in 30% more observing time between the two modes over the course of a year. These additional observations have already allowed for the detection of a flare from the 1ES 1727+502 and for an observing program targeting a measurement of the cosmic-ray positron fraction. We provide details of these new observing modes and their performance relative to the standard VERITAS observations

Evidence for proton acceleration up to TeV energies based on VERITAS and Fermi-LAT observations of the Cas A SNR

We present a study of $\gamma$-ray emission from the core-collapse supernova remnant Cas~A in the energy range from 0.1GeV to 10TeV. We used 65 hours of VERITAS data to cover 200 GeV - 10 TeV, and 10.8 years of \textit{Fermi}-LAT data to cover 0.1-500 GeV. The spectral analysis of \textit{Fermi}-LAT data shows a significant spectral curvature around $1.3 \pm 0.4_{stat}$ GeV that is consistent with the expected spectrum from pion decay. Above this energy, the joint spectrum from \textit{Fermi}-LAT and VERITAS deviates significantly from a simple power-law, and is best described by a power-law with spectral index of $2.17\pm 0.02_{stat}$ with a cut-off energy of $2.3 \pm 0.5_{stat}$ TeV. These results, along with radio, X-ray and $\gamma$-ray data, are interpreted in the context of leptonic and hadronic models. Assuming a one-zone model, we exclude a purely leptonic scenario and conclude that proton acceleration up to at least 6 TeV is required to explain the observed $\gamma$-ray spectrum. From modeling of the entire multi-wavelength spectrum, a minimum magnetic field inside the remnant of $B_{\mathrm{min}}\approx150\,\mathrm{\mu G}$ is deduced.Comment: 33 pages, 9 Figures, 6 Table