Feedback Between Accelerator Physicists and Magnet Builders

Our task is not to record history but to change it. (K. Marx (paraphrased)) How should Accelerator Physicists set magnet error specifications? In a crude social model, they place tolerance limits on undesirable nonlinearities and errors (higher order harmonics, component alignments, etc.). The Magnet Division then goes away for a suitably lengthy period of time, and comes back with a working magnet prototype that is reproduced in industry. A better solution is to set no specifications. Accelerator Physicists begin by evaluating expected values of harmonics, generated by the Magnet Division, before and during prototype construction. Damaging harmonics are traded off against innocuous harmonics as the prototype design evolves, lagging one generation behind the evolution of expected harmonics. Finally, the real harmonics are quickly evaluated during early industrial production, allowing a final round of performance trade-offs, using contingency scenarios prepared earlier. This solution assumes a close relationship and rapid feedback between the Accelerator Physicists and the magnet builders. What follows is one perspective of the way that rapid feedback was used to `change history` (improve linear and dynamic aperture) at RHIC, to great benefit

Grazing function g and collimation angular acceptance

The grazing function g is introduced—a synchrobetatron optical quantity that is analogous (and closely connected) to the Twiss and dispersion functions β, α, η, and η′. It parametrizes the rate of change of total angle with respect to synchrotron amplitude for grazing particles, which just touch the surface of an aperture when their synchrotron and betatron oscillations are simultaneously (in time) at their extreme displacements. The grazing function can be important at collimators with limited acceptance angles. For example, it is important in both modes of crystal collimation operation—in channeling and in volume reflection. The grazing function is independent of the collimator type—crystal or amorphous—but can depend strongly on its azimuthal location. The rigorous synchrobetatron condition g=0 is solved, by invoking the close connection between the grazing function and the slope of the normalized dispersion. Propagation of the grazing function is described, through drifts, dipoles, and quadrupoles. Analytic expressions are developed for g in perfectly matched periodic FODO cells, and in the presence of β or η error waves. These analytic approximations are shown to be, in general, in good agreement with realistic numerical examples. The grazing function is shown to scale linearly with FODO cell bend angle, but to be independent of FODO cell length. The ideal value is g=0 at the collimator, but finite nonzero values are acceptable. Practically achievable grazing functions are described and evaluated, for both amorphous and crystal primary collimators, at RHIC, the SPS (UA9), the Tevatron (T-980), and the LHC

Rf Voltage Modulation At Discrete Frequencies With applications To Crystal channeling Extraction

RF voltage modulation at a finite number of discrete frequencies is described in a Hamiltonian resonance framework. The theory is applied to the problem of parasitic extraction of a fixed target beam from a high energy proton collider, using a bent crystal as a thin ``septum`` within an effective width of about one micron. Three modes of employment of discrete resonances are proposed.First, a single relatively strong static ``drive`` resonance may be used to excite a test proton so that it will penetrate deeply into the channeling crystal. Second, a moderately strong ``feed`` resonance with a ramped modulation tune may be used to adiabatically trap protons near the edge of the beam core, and transport them to the drive resonance. Third, several weak resonances may be overlapped to create a chaotic amplitude band, either to transport protons to the drive resonance, or to provide a ``pulse stretching`` buffer between a feed resonance and the drive resonance. Extraction efficiency is semi- quantitatively described in terms of characteristic ``penetration,`` ``depletion,`` and ``repetition`` times. simulations are used to quantitatively confirm the fundamental results of the theory, and to show that a prototypical extraction scheme using all three modes promises good extraction performance

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Evading the anti-tumour immune response - a novel role for Focal Adhesion Kinase

Here I describe a new function of Focal Adhesion Kinase (FAK) in driving anti-tumour immune evasion. The kinase activity of FAK in squamous cancer cells drives the recruitment of regulatory T-cells (Tregs) by transcriptionally regulating chemokine/cytokine and ligand-receptor networks, including the transcription of CCL5 and TGFβ, which are required for enhanced Treg recruitment. In turn, these changes inhibit antigen-primed cytotoxic CD8+ T-cell activity in the tumour microenvironment, permitting survival and growth of FAK-expressing tumours. I show that immune evasion requires FAK’s catalytic activity, and a small molecule FAK kinase inhibitor, VS-4718, which is currently in clinical development, drives depletion of Tregs and permits CD8+ T-cell-mediated tumour clearance. It is therefore likely that FAK inhibitors may trigger immune-mediated tumour regression, providing previously unrecognized therapeutic benefit