Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System.

Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy

ANSL-V: ENDF/B-V based multigroup cross-section libraries for Advanced Neutron Source (ANS) reactor studies. Supplement 1

The original ANSL-V cross-section libraries (ORNL-6618) were developed over a period of several years for the physics analysis of the ANS reactor, with little thought toward including the materials commonly needed for shielding applications. Materials commonly used for shielding applications include calcium barium, sulfur, phosphorous, and bismuth. These materials, as well as {sup 6}Li, {sup 7}Li, and the naturally occurring isotopes of hafnium, have been added to the ANSL-V libraries. The gamma-ray production and gamma-ray interaction cross sections were completely regenerated for the ANSL-V 99n/44g library which did not exist previously. The MALOCS module was used to collapse the 99n/44g coupled library to the 39n/44g broad- group library. COMET was used to renormalize the two-dimensional (2- D) neutron matrix sums to agree with the one-dimensional (1-D) averaged values. The FRESH module was used to adjust the thermal scattering matrices on the 99n/44g and 39n/44g ANSL-V libraries. PERFUME was used to correct the original XLACS Legendre polynomial fits to produce acceptable distributions. The final ANSL-V 99n/44g and 39n/44g cross-section libraries were both checked by running RADE. The AIM module was used to convert the master cross-section libraries from binary coded decimal to binary format (or vice versa)

Studies on charge production from Cs2Te photocathodes in the PITZ L-band normal conducting radio frequency photo injector

This paper discusses the behavior of electron bunch charge produced in an L-band normal conducting radio frequency cavity (RF gun) from Cs2Te photocathodes illuminated with ps-long UV laser pulses when the laser transverse distribution consists of a flat-top core with Gaussian-like decaying halo. The produced charge shows a linear dependence at low laser pulse energies as expected in the quantum efficiency limited emission regime, while its dependence on laser pulse energy is observed to be much weaker for higher values, due to space charge limited emission. However, direct plug-in of experimental parameters into the space charge tracking code ASTRA yields lower output charge in the space charge limited regime compared to measured values. The rate of increase of the produced charge at high laser pulse energies close to the space charge limited emission regime seems to be proportional to the amount of halo present in the radial laser profile since the charge from the core has saturated already. By utilizing core + halo particle distributions based on measured radial laser profiles, ASTRA simulations and semi-analytical emission models reproduce the behavior of the measured charge for a wide range of RF gun and laser operational parameters within the measurement uncertainties.Comment: 15 pages, 16 figures, 2 table

Reactor physics methods, models, and applications used to support the conceptual design of the Advanced Neutron Source

This report summarizes the neutronics analysis performed during 1991 and 1992 in support of characterization of the conceptual design of the Advanced Neutron Source (ANS). The methods used in the analysis, parametric studies, and key results supporting the design and safety evaluations of the conceptual design are presented. The analysis approach used during the conceptual design phase followed the same approach used in early ANS evaluations: (1) a strong reliance on Monte Carlo theory for beginning-of-cycle reactor performance calculations and (2) a reliance on few-group diffusion theory for reactor fuel cycle analysis and for evaluation of reactor performance at specific time steps over the fuel cycle. The Monte Carlo analysis was carried out using the MCNP continuous-energy code, and the few- group diffusion theory calculations were performed using the VENTURE and PDQ code systems. The MCNP code was used primarily for its capability to model the reflector components in realistic geometries as well as the inherent circumvention of cross-section processing requirements and use of energy-collapsed cross sections. The MCNP code was used for evaluations of reflector component reactivity effects and of heat loads in these components. The code was also used as a benchmark comparison against the diffusion-theory estimates of key reactor parameters such as region fluxes, control rod worths, reactivity coefficients, and material worths. The VENTURE and PDQ codes were used to provide independent evaluations of burnup effects, power distributions, and small perturbation worths. The performance and safety calculations performed over the subject time period are summarized, and key results are provided. The key results include flux and power distributions over the fuel cycle, silicon production rates, fuel burnup rates, component reactivities, control rod worths, component heat loads, shutdown reactivity margins, reactivity coefficients, and isotope production rates

Exploring ultra-low β* values in ATF2 - R&D Programme proposal

We propose to explore the beam sizes and performance of the ATF2 Final Focus System for reduced IP beta functions up to a factor between 2 and 4 below its design. The results will demonstrate the feasibility of the system in a chromaticity regime of interest for CLIC and ILC

Seeing ‘Where’ through the Ears: Effects of Learning-by-Doing and Long-Term Sensory Deprivation on Localization Based on Image-to-Sound Substitution

BACKGROUND: Sensory substitution devices for the blind translate inaccessible visual information into a format that intact sensory pathways can process. We here tested image-to-sound conversion-based localization of visual stimuli (LEDs and objects) in 13 blindfolded participants. METHODS AND FINDINGS: Subjects were assigned to different roles as a function of two variables: visual deprivation (blindfolded continuously (Bc) for 24 hours per day for 21 days; blindfolded for the tests only (Bt)) and system use (system not used (Sn); system used for tests only (St); system used continuously for 21 days (Sc)). The effect of learning-by-doing was assessed by comparing the performance of eight subjects (BtSt) who only used the mobile substitution device for the tests, to that of three subjects who, in addition, practiced with it for four hours daily in their normal life (BtSc and BcSc); two subjects who did not use the device at all (BtSn and BcSn) allowed assessment of its use in the tasks we employed. The impact of long-term sensory deprivation was investigated by blindfolding three of those participants throughout the three week-long experiment (BcSn, BcSn/c, and BcSc); the other ten subjects were only blindfolded during the tests (BtSn, BtSc, and the eight BtSt subjects). Expectedly, the two subjects who never used the substitution device, while fast in finding the targets, had chance accuracy, whereas subjects who used the device were markedly slower, but showed much better accuracy which improved significantly across our four testing sessions. The three subjects who freely used the device daily as well as during tests were faster and more accurate than those who used it during tests only; however, long-term blindfolding did not notably influence performance. CONCLUSIONS: Together, the results demonstrate that the device allowed blindfolded subjects to increasingly know where something was by listening, and indicate that practice in naturalistic conditions effectively improved "visual" localization performance

Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense

Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the''Guard-Hypothesis,'' R proteins (the ``guards'') can sense modification of target molecules in the host (the ``guardees'') by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the ``guardee-effector'' interface for pathogen recognition, natural selection acts on the ``guard-guardee'' interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen

Large scale characterization and calibration strategy of a SiPM-based camera for gamma-ray astronomy

The SST-1M is a 4-m diameter mirror Davies-Cotton gamma-ray telescope. It has been designed to cover the energy range above 500 GeV and to be part of an array of telescopes separated by 150-200 m. Its innovative camera is featuring large area hexagonal silicon photo-multipliers as photon detectors and a fully digital trigger and readout system. Here, the strategy and the methods for its calibration are presented, together with the obtained results. In particular, the off and on-site calibration strategies are demonstrated on the first camera prototype. The performances of the camera in terms of charge and time resolution are described