Optimizing human Treg immunotherapy by Treg subset selection and E-selectin ligand expression

While human Tregs hold immense promise for immunotherapy, their biologic variability poses challenges for clinical use. Here, we examined clinically-relevant activities of defined subsets of freshly-isolated and culture-expanded human PBMC-derived Tregs. Unlike highly suppressive but plastic memory Tregs (memTreg), naïve Tregs (nvTreg) exhibited the greatest proliferation, suppressive capacity after stimulation, and Treg lineage fidelity. Yet, unlike memTregs, nvTregs lack Fucosyltransferase VII and display low sLeX expression, with concomitant poor homing capacity. In vitro nvTreg expansion augmented their suppressive function, but did not alter the nvTreg sLeX-l ° w glycome. However, exofucosylation of the nvTreg surface yielded high sLeX expression, promoting endothelial adhesion and enhanced inhibition of xenogeneic aGVHD. These data indicate that the immature Treg glycome is under unique regulation and that adult PBMCs can be an ideal source of autologous-derived therapeutic Tregs, provided that subset selection and glycan engineering are engaged to optimize both their immunomodulation and tropism for inflammatory sites

Inherited variation in immune genes and pathways and glioblastoma risk

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel–Haenzel P values = 1 × 10−5 to 4 × 10−3), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion–extravasation–migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk

Assessing and managing natural risks at the Panama Canal

The Panama Canal Authority (ACP) has undertaken a comprehensive assessment of natural and chronic risks to improve planning and to optimize its engineering safeguards. The risk assessment program began with an all-inclusive risk register. The register lists somewhat more than 500 items divided among the many categories of facilities constituting the Canal (dams, locks, cuts, gates, power stations, water plants, and others) and among the various hazards facing the Canal (seismic, hydrologic, meteorological, operational). Scientific and operations data for the Canal have been compiled to characterize risk, while modern reliability models have been developed to translate those data into actionable assessments of reliability and consequence. Risks were categorized as catastrophic, significant, or moderate. The first set has been engineered in detail; the others have been approached operationally. The resulting probabilities and consequences are tracked in acceptable risk charts in FN format better to understand where risk remediation is called for. This comprehensive risk assessment is allowing ACP to reduce risk while meaningly keeping costs under control.Non UBCUnreviewedThis collection contains the proceedings of ICASP12, the 12th International Conference on Applications of Statistics and Probability in Civil Engineering held in Vancouver, Canada on July 12-15, 2015. Abstracts were peer-reviewed and authors of accepted abstracts were invited to submit full papers. Also full papers were peer reviewed. The editor for this collection is Professor Terje Haukaas, Department of Civil Engineering, UBC Vancouver.FacultyOthe

CAPTCHAs: The Good, the Bad, and the Ugly

www.minicrypt.de Abstract. A CAPTCHA is a program that generates challenges that are easy to solve for humans but difficult to solve for computers. The most common CAPTCHAs today are text-based ones where a short word is embedded in a cluttered image. In this paper, we survey the state-of-the-art of currently deployed CAPTCHAs, especially of some popular German sites. Surprisingly, despite their importance and the largescale deployment, most of the CAPTCHAs like the ones of the “Umweltprämie”, the Bundesfinanzagentur, and the Sparda-Bank are rather weak. Our results show that these CAPTCHAs are subject to automated attacks solving up to 80 % of the puzzles. Furthermore, we suggest design criteria for “good ” CAPTCHAs and for the system using them. In light of this we revisit the popular reCAPTCHA system and latest developments about its security. Finally, we discuss some alternative approaches for CAPTCHAs.