Snowmass 2021 Underground Facilities & Infrastructure Frontier Report

The decade since Snowmass 2013 has seen extraordinary progress of high energy physics research performed--or planned for--at underground facilities. Drs. T. Kajita and A.B. McDonald were awarded the 2015 Nobel Prize in Physics for the discovery of neutrino oscillation, which show that neutrinos have mass. The U.S. has embarked on the development of the world-class LBNF/DUNE science program to investigate neutrino properties. The Generation 2 dark matter program is advancing to full data collection in the coming 5 years, a Dark Matter New Initiatives program has begun, and the U.S. dark matter community is looking toward a Generation 3 program of large-scale dark matter direct detection searches. The Sanford Underground Research Facility has become a focal point for U.S. underground facilities and infrastructure investment. The status since the 2013 Snowmass process as well as the outcome from the 2014 P5 program of recommendations is reviewed. These are then evaluated based on the activities and discussions of the Snowmass 2021 process resulting in conclusions looking forward to the coming decade of high energy physics research performed in underground facilities.Comment: Snowmass 2021 Underground Facilities & Infrastructure Frontier Repor

Nuclear Physics Neutrino PreTown Meeting: Summary and Recommendations

In preparation for the nuclear physics Long Range Plan exercise, a group of 104 neutrino physicists met in Seattle September 21-23 to discuss both the present state of the field and the new opportunities of the next decade. This report summarizes the conclusions of that meeting and presents its recommendations. Further information is available at the workshop's web site. This report will be further reviewed at the upcoming Oakland Town Meeting.Comment: Latex, 31 pages. This version has been updated to include final Comments from the working group

Deep Underground Science and Engineering Laboratory - Preliminary Design Report

The DUSEL Project has produced the Preliminary Design of the Deep Underground Science and Engineering Laboratory (DUSEL) at the rehabilitated former Homestake mine in South Dakota. The Facility design calls for, on the surface, two new buildings - one a visitor and education center, the other an experiment assembly hall - and multiple repurposed existing buildings. To support underground research activities, the design includes two laboratory modules and additional spaces at a level 4,850 feet underground for physics, biology, engineering, and Earth science experiments. On the same level, the design includes a Department of Energy-shepherded Large Cavity supporting the Long Baseline Neutrino Experiment. At the 7,400-feet level, the design incorporates one laboratory module and additional spaces for physics and Earth science efforts. With input from some 25 science and engineering collaborations, the Project has designed critical experimental space and infrastructure needs, including space for a suite of multidisciplinary experiments in a laboratory whose projected life span is at least 30 years. From these experiments, a critical suite of experiments is outlined, whose construction will be funded along with the facility. The Facility design permits expansion and evolution, as may be driven by future science requirements, and enables participation by other agencies. The design leverages South Dakota's substantial investment in facility infrastructure, risk retirement, and operation of its Sanford Laboratory at Homestake. The Project is planning education and outreach programs, and has initiated efforts to establish regional partnerships with underserved populations - regional American Indian and rural populations

Electrical Signal Path Study and Component Assay for the MAJORANA N-Type Segmented Contact Detector

The purpose of the present electrical signal path study is to explore the various issues related to the deployment of highly-segmented low-background Ge detectors for the MAJORANA double-beta decay experiment. A significant challenge is to simultaneously satisfy competing requirements for the mechanical design, electrical readout performance, and radiopurity specifications from the MAJORANA project. Common to all rare search experiments, there is a very stringent limit on the acceptable radioactivity level of all the electronics components involved. Some of the findings are summarized in this report

Report of the 2021 U.S. Community Study on the Future of Particle Physics (Snowmass 2021) Summary Chapter

The 2021-22 High-Energy Physics Community Planning Exercise (a.k.a. ``Snowmass 2021'') was organized by the Division of Particles and Fields of the American Physical Society. Snowmass 2021 was a scientific study that provided an opportunity for the entire U.S. particle physics community, along with its international partners, to identify the most important scientific questions in High Energy Physics for the following decade, with an eye to the decade after that, and the experiments, facilities, infrastructure, and R&D needed to pursue them. This Snowmass summary report synthesizes the lessons learned and the main conclusions of the Community Planning Exercise as a whole and presents a community-informed synopsis of U.S. particle physics at the beginning of 2023. This document, along with the Snowmass reports from the various subfields, will provide input to the 2023 Particle Physics Project Prioritization Panel (P5) subpanel of the U.S. High-Energy Physics Advisory Panel (HEPAP), and will help to guide and inform the activity of the U.S. particle physics community during the next decade and beyond.Comment: 75 pages, 3 figures, 2 tables. This is the first chapter and summary of the full report of the Snowmass 2021 Workshop. This version fixes an important omission from Table 2, adds two references that were not available at the time of the original version, fixes a minor few typos, and adds a small amount of material to section 1.1.

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

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

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution