Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma

Gene electrotransfer (GET) is a safe, reliable, and effective method of delivering plasmid DNA (pDNA) to solid tumors. GET has been previously used to deliver interleukin-15 (IL-15) to mouse melanoma, resulting in long-term tumor regression and the survival of a percentage of treated animals after challenge. To enhance this effect, we evaluated modulating the expression levels of IL-15 and co-expressing its receptor, IL-15Rα. GET was used to deliver plasmids encoding IL-15 and IL-15Rα to established B16.F10 tumors on days 0, 4, and 7. Two delivery protocols that yielded different expression profiles were utilized. Mice that were tumor-free for 50 days were then challenged with B16.F10 cells on the opposite flank and monitored for an additional 50 days. The amount of IL-15 expressed and the presence or absence of IL-15Rα in the treated tumors did not significantly affect the tumor regression and long-term survival. Upon challenge, however, low levels of IL-15 were more protective and resulted in a greater production of anti-tumor cytokines such as IFN-γ and MIP-1β and a greater amount of CD11b+ and CD3e+ cells infiltrating tumors. While mice with high levels of IL-15 showed CD11b+ and CD3e+ cell infiltrate, there was a substantial presence of NK cells that was absent in other treated groups. We can conclude that the level of IL-15 expressed in tumors after GET is an important determinant of the therapeutic outcome, a finding that will help us finetune this type of therapy

Sampling, Intervention, Prediction, Aggregation: A Generalized Framework for Model-Agnostic Interpretations

Model-agnostic interpretation techniques allow us to explain the behavior of any predictive model. Due to different notations and terminology, it is difficult to see how they are related. A unified view on these methods has been missing. We present the generalized SIPA (sampling, intervention, prediction, aggregation) framework of work stages for model-agnostic interpretations and demonstrate how several prominent methods for feature effects can be embedded into the proposed framework. Furthermore, we extend the framework to feature importance computations by pointing out how variance-based and performance-based importance measures are based on the same work stages. The SIPA framework reduces the diverse set of model-agnostic techniques to a single methodology and establishes a common terminology to discuss them in future work

Fractional Loop Group and Twisted K-Theory

We study the structure of abelian extensions of the group $L_qG$ of $q$-differentiable loops (in the Sobolev sense), generalizing from the case of central extension of the smooth loop group. This is motivated by the aim of understanding the problems with current algebras in higher dimensions. Highest weight modules are constructed for the Lie algebra. The construction is extended to the current algebra of supersymmetric Wess-Zumino-Witten model. An application to the twisted K-theory on $G$ is discussed.Comment: Final version in Commun. Math. Phy

Wave function mapping conditions in Open Quantum Dots structures

We discuss the minimal conditions for wave function spectroscopy, in which resonant tunneling is the measurement tool. Two systems are addressed: resonant tunneling diodes, as a toy model, and open quantum dots. The toy model is used to analyze the crucial tunning between the necessary resolution in current-voltage characteristics and the breakdown of the wave functions probing potentials into a level splitting characteristic of double quantum wells. The present results establish a parameter region where the wavefunction spectroscopy by resonant tunneling could be achieved. In the case of open quantum dots, a breakdown of the mapping condition is related to a change into a double quantum dot structure induced by the local probing potential. The analogy between the toy model and open quantum dots show that a precise control over shape and extention of the potential probes is irrelevant for wave function mapping. Moreover, the present system is a realization of a tunable Fano system in the wave function mapping regime.Comment: 6 pages, 6 figure

Vascular Endothelial Growth Factor-A Gene Electrotransfer Promotes Angiogenesis in a Porcine Model of Cardiac Ischemia

This study aimed to assess safety and therapeutic potential of gene electrotransfer (GET) as a method for delivery of plasmid encoding vascular endothelial growth factor A (VEGF-A) to ischemic myocardium in a porcine model. Myocardial ischemia was induced by surgically occluding the left anterior descending coronary artery in swine. GET following plasmid encoding VEGF-A injection was performed at four sites in the ischemic region. Control groups either received injections of the plasmid without electrotransfer or injections of the saline vehicle. Animals were monitored for 7 weeks and the hearts were evaluated for angiogenesis, myocardial infarct size and left ventricular contractility. Arteriograms suggest growth of new arteries as early as 2 weeks after treatment in electrotransfer animals. There is a significant reduction of infarct area and left ventricular contractility is improved in GET-treated group compared with controls. There was no significant difference in mortality of animals treated with GET of plasmid encoding VEGF-A from the control groups. Gene delivery of plasmid encoding VEGF-A to ischemic myocardium in a porcine model can be accomplished safely with potential for myocardial repair and regeneration

Time ordering and counting statistics

The basic quantum mechanical relation between fluctuations of transported charge and current correlators is discussed. It is found that, as a rule, the correlators are to be time-ordered in an unusual way. Instances where the difference with the conventional ordering matters are illustrated by means of a simple scattering model. We apply the results to resolve a discrepancy concerning the third cumulant of charge transport across a quantum point contact.Comment: 19 pages, 1 figure; inconsequential mistake and typos correcte

Robust decision-making under severe uncertainty for conservation management

In-conservation biology it is necessary to make management decisions for endangered and threatened species under severe uncertainty. Failure to acknowledge and treat uncertainty can lead to poor decisions. To illustrate the importance of considering uncertainty, we reanalyze a decision problem for the Sumatran rhino, Dicerorhinus sumatrensis, using information-gap theory to propagate uncertainties and to rank management options. Rather than requiring information about the extent of parameter uncertainty at the outset, information-gap theory addresses the question of how much uncertainty can be tolerated before our decision would change. It assesses the robustness of decisions in the face of severe uncertainty. We show that different management decisions may result when uncertainty in utilities and probabilities are considered in decision-making problems. We highlight the importance of a full assessment of uncertainty in conservation management decisions to avoid, as much as possible, undesirable outcomes

The substantive and practical significance of citation impact differences between institutions: Guidelines for the analysis of percentiles using effect sizes and confidence intervals

In our chapter we address the statistical analysis of percentiles: How should the citation impact of institutions be compared? In educational and psychological testing, percentiles are already used widely as a standard to evaluate an individual's test scores - intelligence tests for example - by comparing them with the percentiles of a calibrated sample. Percentiles, or percentile rank classes, are also a very suitable method for bibliometrics to normalize citations of publications in terms of the subject category and the publication year and, unlike the mean-based indicators (the relative citation rates), percentiles are scarcely affected by skewed distributions of citations. The percentile of a certain publication provides information about the citation impact this publication has achieved in comparison to other similar publications in the same subject category and publication year. Analyses of percentiles, however, have not always been presented in the most effective and meaningful way. New APA guidelines (American Psychological Association, 2010) suggest a lesser emphasis on significance tests and a greater emphasis on the substantive and practical significance of findings. Drawing on work by Cumming (2012) we show how examinations of effect sizes (e.g. Cohen's d statistic) and confidence intervals can lead to a clear understanding of citation impact differences