Using low voltage ionization chamber (LVIC) in current mode for energy spectrum reconstruction: Experiments and validation.

Due to the International Thermonuclear Experimental Reactor (ITER) radiative environment, in particular during high D-T power phase, classic x-ray detectors, such as semiconductor diodes, might be too fragile and are thus not viable. Instead, robust detectors, such as gas-filled detectors, are nowadays considered. The Low Voltage Ionization Chamber (LVIC) is one of the most promising candidates for x-ray measurement during the ITER nuclear phase. A complete model of the detector, recently developed at IRFM (Intitute for Research on Magnetic Fusion), now requires experimental validation. Experimental testing at the IRFM laboratory of an ITER industrial LVIC prototype and comparison with modeling are presented. In particular, an original approach to extract information on the x-ray spectrum from current-mode LVIC measurement is validated experimentally.

Intratumoral expression of IL-12 from lentiviral or RNA vectors acts synergistically with TLR4 agonist (GLA) to generate anti-tumor immunological memory.

Systemic interleukin-12 (IL12) anti-tumor therapy is highly potent but has had limited utility in the clinic due to severe toxicity. Here, we present two IL12-expressing vector platforms, both of which can overcome the deficiencies of previous systemic IL12 therapies: 1) an integrating lentiviral vector, and 2) a self-replicating messenger RNA formulated with polyethyleneimine. Intratumoral administration of either IL12 vector platform resulted in recruitment of immune cells, including effector T cells and dendritic cells, and the complete remission of established tumors in multiple murine models. Furthermore, concurrent intratumoral administration of the synthetic TLR4 agonist glucopyranosyl lipid A formulated in a stable emulsion (GLA-SE) induced systemic memory T cell responses that mediated complete protection against tumor rechallenge in all survivor mice (8/8 rechallenged mice), whereas only 2/6 total rechallenged mice treated with intratrumoral IL12 monotherapy rejected the rechallenge. Taken together, expression of vectorized IL12 in combination with a TLR4 agonist represents a varied approach to broaden the applicability of intratumoral immune therapies of solid tumors.

Conceptual study of energy resolved x-ray measurement and electron temperature reconstruction on ITER with low voltage ionization chambers.

In tokamaks with tungsten-based plasma facing components, such as ITER, pollution of the plasma by heavy impurities is a major concern as it can lead to radiative breakdown. The radiation emitted by such impurities is mainly composed of x-rays in the [0.1; 100] keV range. A diagnostic allowing for the reconstruction of the impurity distribution is of high interest. The ITER requirements for the x-ray measurement system make it mandatory for the detector to provide spectral information. Due to the radiation environment during the ITER nuclear phase, advanced detectors exhibiting high resilience to neutrons and gamma rays, such as gas-filled detectors, are required. The use of Low Voltage Ionization Chambers (LVICs) for this purpose is investigated in this paper. Several anodes have been added to the detector in order to allow for spectral deconvolution. This article presents a conceptual study of the use of a multi-anode LVIC for energy resolved x-ray measurement on ITER. It covers the design of the multi-anode LVIC and its modeling, the method for spectral deconvolution, and its application to energy resolved x-ray tomography, as well as the computation of the electron temperature from the reconstructed local x-ray emissivity.

Modeling a low voltage ionization chamber based tomography system on ITER.

Soft x-ray (SXR) tomography is a key diagnostic method for impurity transport study in tokamaks since it allows for local impurity density reconstruction. The International Thermonuclear Experimental Reactor (ITER) radiative environment in deuterium-deuterium and deuterium-tritium phases will limit the choices of SXR detector technologies, and gas detectors are one of the most promising solutions. In this paper, we, thus, investigate the SXR tomography possibilities on ITER using Low Voltage Ionization Chambers (LVICs). The study contains the development of a LVIC synthetic diagnostic and its application to estimate the LVIC tomographic capabilities in an ITER D-T scenario, including the influence of LVIC parameters and noise in the measurements.

ZVex™, a dendritic-cell-tropic lentivector, primes protective antitumor T cell responses that are significantly boosted using heterologous vaccine modalities.

Therapeutic cancer vaccines must induce high levels of tumor-specific cytotoxic CD8 T cells to be effective. We show here that tumor-antigen specific effector and memory T cell responses primed with a non-integrating, dendritic-cell targeted lentiviral vector (ZVex™) could be boosted significantly by either adjuvanted recombinant protein, adenoviral vectors, or self-replicating RNA. These heterologous prime-boost regimens also provided significantly better protection in murine tumor models. In contrast, homologous prime-boost regimens, or using the lentiviral vector as a boost, resulted in lower T cell responses with limited therapeutic efficacy. Heterologous prime-boost regimens that utilize ZVex as the prime may be attractive modalities for therapeutic cancer vaccines.

Incorporating magnetic equilibrium information in Gaussian process tomography for soft X-ray spectroscopy at WEST.

Gaussian process tomography (GPT) [J. Svensson, JET Internal Report EFDA-JET-PR(11)24, 2011 and D. Li, J. Svensson, H. Thomsen, F. Medina, A. Werner, and R. Wolf, Rev. Sci. Instrum. 84, 083506 (2013)] is a recently developed tomography method applied earlier to soft X-ray (SXR) spectroscopy on WEST-Tungsten (W) Environment in Steady-state Tokamak. The short execution time of the algorithm makes GPT an important candidate for providing real-time information on impurity transport and for fast MHD control. In earlier work, GPT has shown its flexibility by providing good reconstruction results without background information about the magnetic equilibrium. On the other hand, information about the magnetic flux surface geometry can in general be useful for additional regularization of the solution. In this paper, we develop a way to take into account the equilibrium information, by constructing a covariance matrix of the prior Gaussian process depending on the flux surface geometry. The GPT method is validated using synthetic SXR emissivity profiles relevant to WEST plasmas and compares favorably with the classical algorithm based on minimization of the Fisher information.

Gaussian process tomography for soft x-ray spectroscopy at WEST without equilibrium information.

Gaussian process tomography (GPT) is a recently developed tomography method based on the Bayesian probability theory [J. Svensson, JET Internal Report EFDA-JET-PR(11)24, 2011 and Li et al., Rev. Sci. Instrum. 84, 083506 (2013)]. By modeling the soft X-ray (SXR) emissivity field in a poloidal cross section as a Gaussian process, the Bayesian SXR tomography can be carried out in a robust and extremely fast way. Owing to the short execution time of the algorithm, GPT is an important candidate for providing real-time reconstructions with a view to impurity transport and fast magnetohydrodynamic control. In addition, the Bayesian formalism allows quantifying uncertainty on the inferred parameters. In this paper, the GPT technique is validated using a synthetic data set expected from the WEST tokamak, and the results are shown of its application to the reconstruction of SXR emissivity profiles measured on Tore Supra. The method is compared with the standard algorithm based on minimization of the Fisher information.

Biophysical Attributes of CpG Presentation Control TLR9 Signaling to Differentially Polarize Systemic Immune Responses.

It is currently unknown whether and how mammalian pathogen recognition receptors (PRRs) respond to biophysical patterns of pathogen-associated molecular danger signals. Using synthetic pathogen-like particles (PLPs) that mimic physical properties of bacteria or large viruses, we have discovered that the quality and quantity of Toll-like receptor 9 (TLR9) signaling by CpG in mouse dendritic cells (mDCs) are uniquely dependent on biophysical attributes; specifically, the surface density of CpG and size of the presenting PLP. These physical patterns control DC programming by regulating the kinetics and magnitude of MyD88-IRAK4 signaling, NF-κB-driven responses, and STAT3 phosphorylation, which, in turn, controls differential T cell responses and in vivo immune polarization, especially T helper 1 (Th1) versus T helper 2 (Th2) antibody responses. Our findings suggest that innate immune cells can sense and respond not only to molecular but also pathogen-associated physical patterns (PAPPs), broadening the tools for modulating immunity and helping to better understand innate response mechanisms to pathogens and develop improved vaccines.

Surface-Presentation of CpG and Protein-Antigen on Pathogen-Like Polymer Particles Generate Strong Prophylactic and Therapeutic Antitumor Protection.

Despite significant efforts, development of clinically relevant prophylactic and therapeutic cancer vaccines has proven challenging. Cancer-associated antigens, which are often self-antigens, do not activate innate immune cells sufficiently, underscoring the need for codelivery of appropriate immune-stimulatory adjuvants. Recent research has underscored the need for biomaterial-based carriers for vaccine delivery, not only to target antigens and adjuvants to antigen-presenting cells or to create "depot" like systems but also to avoid acute systemic toxicity of molecular adjuvants that occurs when adjuvants are delivered in their "naked" form. The work presented here focuses on surface-presentation of both antigens and adjuvants on a pathogen-like particle (PLP) platform and understanding how PLP-induced antitumor responses differ when protein antigens and adjuvants, specifically the TLR9 agonist CpG, are delivered on the surface of the same particle (dual-loaded) versus being codelivered on separate particles. Surface-presentation allows easier access of antigens and adjuvants to intracellular targets (e.g., to TLR9 in the phagosomal compartments) and also allows controlled multivalent presentation. Our results show that, surface presentation, as opposed to soluble molecules, was more efficient in activating dendritic cells (DCs) and polarizing them toward generating a stronger cytotoxic T cell response. Signaling and DC polarization between separate and dual-loaded particles were similar, although NF-kB signaling at higher doses was stronger in dual-loaded PLPs. In vivo, dual loaded PLPs performed better than separately loaded PLPs in a prophylactic tumor model of melanoma and were comparable to immunization using incomplete Freud's adjuvant (IFA). In contrast both PLP-based delivery modalities performed similarly in a therapeutic melanoma-vaccine model and significantly outperformed IFA-based vaccination. These results indicate that surface-presentation of antigens and adjuvants on polymer-particles is a promising modality for efficient anticancer vaccines.

Polycapillary lenses for soft x-ray transmission in ITER: Model, comparison with experiments, and potential application.

Measuring Soft X-Ray (SXR) radiation [0.1 keV; 15 keV] in tokamaks is a standard way of extracting valuable information on the particle transport and magnetohydrodynamic activity. Generally, the analysis is performed with detectors positioned close to the plasma for a direct line of sight. A burning plasma, like the ITER deuterium-tritium phase, is too harsh an environment to permit the use of such detectors in close vicinity of the machine. We have thus investigated in this article the possibility of using polycapillary lenses in ITER to transport the SXR information several meters away from the plasma in the complex port-plug geometry.

Gaseous electron multiplier-based soft x-ray plasma diagnostics development: Preliminary tests at ASDEX Upgrade.

A Gaseous Electron Multiplier (GEM)-based detector is being developed for soft X-ray diagnostics on tokamaks. Its main goal is to facilitate transport studies of impurities like tungsten. Such studies are very relevant to ITER, where the excessive accumulation of impurities in the plasma core should be avoided. This contribution provides details of the preliminary tests at ASDEX Upgrade (AUG) with a focus on the most important aspects for detector operation in harsh radiation environment. It was shown that both spatially and spectrally resolved data could be collected, in a reasonable agreement with other AUG diagnostics. Contributions to the GEM signal include also hard X-rays, gammas, and neutrons. First simulations of the effect of high-energy photons have helped understanding these contributions.

The effect of combined IL10 siRNA and CpG ODN as pathogen-mimicking microparticles on Th1/Th2 cytokine balance in dendritic cells and protective immunity against B cell lymphoma.

Success of an immunotherapy for cancer often depends on the critical balance of T helper 1 (Th1) and T helper 2 (Th2) responses driven by antigen presenting cells, specifically dendritic cells (DCs). Th1-driven cytotoxic T cell (CTL) responses are key to eliminating tumor cells. It is well established that CpG oligonucleotides (ODN), a widely studied Toll-like receptor 9 (TLR9) agonist, used to enhance Th1 response, also induces high levels of the anti-inflammatory, Th2-promoting cytokine IL10, which could dampen the resulting Th1 response. Biomaterials-based immunomodulatory strategies that can reduce IL10 production while maintaining IL12 levels during CpG delivery could further enhance the Th1/Th2 cytokine balance and improve anti-tumor immune response. Here we report that dual-delivery of IL10-silencing siRNA along with CpG ODN to the same DCs using pathogen-mimicking microparticles (PMPs), significantly enhances their Th1/Th2 cytokine ratio through concurrent inhibition of CpG-induced IL10 production. Co-delivery of poly(I:C), a TLR3 agonist had only minor effects on IL10 levels. Further, simultaneous immunotherapy with CpG ODN and IL10 siRNA enhanced immune protection of an idiotype DNA vaccine in a prophylactic murine model of B cell lymphoma whereas co-delivery of poly(I:C) and CpG did not enhance protection. These results suggest that PMPs can be used to precisely modulate TLR ligand-mediated immune-stimulation in DCs, through co-delivery of cytokine-silencing siRNAs and thereby boost antitumor immunity.

René Küss (1913-2006)-a transplant pioneer in Paris.

René Küss (1913-2006), an outstanding urologic surgeon, was one of the leading pioneers in kidney transplantation. He suggested and perfected the retroperitoneal placement of the donor kidney into the iliac fossa and its anastomosis to the iliac vessels in the early 1950s. He was one of the first to introduce an immunosuppressive regimen in kidney transplantation a decade later. Küss established the first multiple department of urology at the Paris hospitals, served as General Secretary and later as President for the Société Internationale d'Urologie from 1952 until 1985, and founded "La Société Francaise de Transplantation" as the first scientific society dedicated to transplantation medicine in Europe in 1971. Moreover, Küss was an art connoisseur and collector, an automobiliste, and a medical historian.

Prognostic model for total mortality in patients with haemodialysis from the Assessments of Survival and Cardiovascular Events (AURORA) study.

OBJECTIVES: Risk factors of mortality in patients with haemodialysis (HD) have been identified in several studies, but few prognostic models have been developed with assessments of calibration and discrimination abilities. We used the database of the Assessment of Survival and Cardiovascular Events study to develop a prognostic model of mortality over 3-4 years. METHODS: Five factors (age, albumin, C-reactive protein, history of cardiovascular disease and diabetes) were selected from experience and forced into the regression equation. In a 67% random try-out sample of patients, no further factors amongst 24 candidates added significance (P < 0.01) to mortality outcome as assessed by Cox regression modelling, and individual probabilities of death were estimated in the try-out and test samples. Calibration was explored by calculating the prognostic index with regression coefficients from the try-out sample to patients in the 33% test sample. Discrimination was assessed by receiver operating characteristic (ROC) areas. RESULTS: The strongest prognostic factor in the try-out sample was age, with small differences between the other four factors. Calibration in the test sample was good when the calculated number of deaths was multiplied by a constant of 1.33. The five-factor model discriminated reasonably well between deceased and surviving patients in both the try-out and test samples with an ROC area of about 0.73. CONCLUSIONS: A model consisting of five factors can be used to estimate and stratify the probability of death for individuals The model is most useful for long-term prognosis in an HD population with survival prospects of more than 1 year.

A medical simulator for subcutaneous contraceptive implant insertion.

New contraceptive methods like the subcutaneous implant offers a new kind of comfort for women with an efficiency similar to the contraceptive pill. Unfortunately the few numbers of unintended pregnancies that have been reported are generally due to a bad insertion of the implant. In order to give more security to patients, we have designed, in close collaboration with physicians, a new kind of medical simulator. This paper focuses on a device dedicated to a specific subcutaneous implant but it is worth noting that this simulator is relatively generic since it will be used for other subcutaneous techniques or other implant instruments. This simulator can be used for two purposes: one for training novice physicians in the correct manipulation and the other for physician certification which will help determine if they are capable of inserting the implant in vivo. This paper describes the approach which has led to the design of this simulator. It describes its functionalities, its several components but also methods used to analyze the manipulation of the implant insertion inside the patient. Finally first experimental results are reported and discussed. The system used in this paper makes possible to carry out training in a constraint-free context and provides the first mean of visualizing a maneuver that, until now, has been performed blindly.

Design of a medical simulator for subcutaneous contraceptive implant insertion.

New contraceptive methods like the subcutaneous implant offers a new kind of comfort for women with an efficiency similar to the contraceptive pill. Unfortunately, the few numbers of unintended pregnancies that have been reported, are generally due to a bad insertion of the implant. In order to give more security to patients, we have designed, in close collaboration with physicians, a new kind of medical simulator. This simulator can be used for two purposes: one for training novice physicians in the correct gesture and the other for doctor certification which will help to determine if they are capable of inserting the implant in vivo. This paper describes the approach which has led to the design of this simulator. It describes its functionalities, its several components but also methods used to analyze the gesture of the implant insertion inside the patient. Finally, first experimental results are reported and discussed.