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Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47–not estimable [NE]) with nivolumab and 19·53 months (2·33–NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31–2·54); median time to progression was 9·4 months (95% CI 1·47–NE) in the nivolumab group and 19·53 months (2·33–NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31–2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. Funding: Bristol Myers Squibb and the US National Institutes of Health.

RMP1-14 is a monoclonal antibody that targets the murine PD-1 protein, and has been used extensively to probe the effects of PD-1 inhibition in preclinical murine models. However, to date, no quantitative analytical methods have been published for RMP1-14. To evaluate its anti-tumor activity in BALB/c mice inoculated with CT26.WT murine colon cancer cells, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify RMP1-14 in BALB/c mouse K3EDTA plasma was developed and validated. The methodology used a signature peptide (GFYPPDIYTEWK) as a surrogate for RMP1-14 quantitation and an isotopically labeled analog of the signature peptide as the internal standard. Initial method development focused on a hybrid LC-MS/MS assay involving Protein G immunoprecipitation, but this strategy was abandoned due to lack of selectivity. The final validated method consisted of dilution with Tris-buffered saline, trypsin digestion, and desalting using micro solid-phase extraction. Analytical run time was 3.50 min, and the method demonstrated linearity between 0.500 and 50.0 μg/mL of intact RMP1-14. Accuracy, precision, and robustness were all acceptable, and the method was demonstrated to be comparable to a commercially available fit-for-purpose enzyme-linked immunosorbent assay (ELISA) capable of measuring RMP1-14. The validated method was used to generate pharmacokinetic parameters from tumor-bearing BALB/c mice dosed with RMP1-14 at either 2.50 or 7.50 mg/kg. Overall, the validated method represents a novel tool that can be used to evaluate RMP1-14 activity in future immuno-oncology studies.

The Radio Neutrino Observatory Greenland (RNO-G) is scheduled for deployment in the summerof 2021. It will target the detection of astrophysical and cosmogenic neutrinos above 10 PeV. With 35 autonomous stations, it will be the largest implementation of a radio neutrino detector to date.The stations combine best-practice instrumentation from all previous radio neutrino arrays, such as a deep phased-array trigger and surface antennas. These proceedings describe the experimentalconsiderations that have driven the design of RNO-G and the current progress in deployment, aswell as discuss the projected sensitivity of the instrument. RNO-G will provide a unique view ofthe Northern Sky and will also inform the design of the radio component of IceCube-Gen2.

The Askaryan Radio Array (ARA) is a ground-based radio detector at the South Pole designed to capture Askaryan emission from ultra-high energy neutrinos interacting within the Antarctic ice. The newest ARA station has been equipped with a phased array trigger, in which radio signals in multiple antennas are summed in predetermined directions prior to the trigger. In this way, impulsive signals add coherently, while noise likely does not, allowing the trigger threshold to be lower than a traditional ARA station. Early results on just a fraction of available data from this new system prove the feasibility of a low-threshold analysis.

The Askaryan Radio Array (ARA) is an ultra-high energy (UHE) neutrino ($E_{\nu}$ > $10^{17}$ eV) detector at South Pole. ARA aims to utilize radio signals detected from UHE neutrino interactions in the glacial ice to infer properties about the interaction vertex as well as the incident neutrino. To retrieve these properties from experiment data, the first step is to extract timing, amplitude and frequency information from waveforms of different antennas buried in the deep ice. These features can then be utilized in a neural network to reconstruct the neutrino interaction vertex position, incoming neutrino direction and shower energy. So far, vertex can be reconstructed through interferometry while neutrino reconstruction is still under investigation. Here I will present a solution based on multi-task deep neural networks which can perform reconstruction of both vertex and incoming neutrinos with a reasonable precision. After training, this solution is capable of rapid reconstructions (e.g. 0.1 ms/event compared to 10000 ms/event in a conventional routine) useful for trigger and filter decisions, and can be easily generalized to different station configurations for both design and analysis purposes.

Owing to their small interaction cross-section, neutrinos are unparalleled astronomical tracers. Ultra-high energy (UHE; E > 10 PeV) neutrinos probe the most distant, most explosive sources in the Universe, often obscured to optical telescopes. Radio-frequency (RF) detection of Askaryan radiation in cold polar ice is currently regarded as the best experimental measurement technique for UHE neutrinos, provided the RF properties of the ice target can be well-understood. To that end, the Askaryan Radio Array (ARA) experiment at the South Pole has used long-baseline RF propagation to extract information on the index-of-refraction ( n = ϵ r ) in South Polar ice. Owing to the increasing ice density over the upper 150–200 m, rays are measured along two, nearly parallel paths, one of which refracts through an inflection point, with differences in both arrival time and arrival angle that can be used to constrain the neutrino properties. We also observe (first) indications for RF ice birefringence for signals propagating along predominantly horizontal trajectories, corresponding to an asymmetry of order 0.1% between the ordinary and extra-ordinary birefringent axes, numerically compatible with previous measurements of birefringent asymmetries for vertically-propagating radio-frequency signals at South Pole. Qualitatively, these effects offer the possibility of redundantly measuring the range from receiver to a neutrino interaction in Antarctic ice, if receiver antennas are deployed at shallow (z ∼ −25 m) depths. Such range information is essential in determining both the neutrino energy, as well as the incident neutrino direction.

The NASA supported High-Altitude Calibration (HiCal)-2 instrument flew as a companion balloon to the ANITA-4 experiment in December 2016. Based on a HV discharge pulser producing radio-frequency (RF) calibration pulses, HiCal-2 comprised two payloads, which flew for a combined 18 days, covering 1.5 revolutions of the Antarctic continent. ANITA-4 captured over 10,000 pulses from HiCal, both direct and reflected from the surface, at distances varying from 100-800 km, providing a large dataset for surface reflectivity measurements. Herein we present details on the design, construction and performance of HiCal-2., Comment: Published in NIM-A, final version

Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. However, advanced prostate cancer is difficult to treat due to a lack of effective approaches for disrupting immune tolerance. RM-1 is a murine prostate cancer cell line derived from a Ras/Myc-induced prostate cancer. RM-1 is of particular interest because it is an aggressive, nonimmunogenic, potentially metastatic prostate line that is androgen independent. Subcutaneous growth kinetics were evaluated for RM-1 cells implanted at two cell inocula (1.0E+06 and 5.0E+05 cells/implant). RM-1 grew aggressively across both implant conditions, producing 100% take rate, a median tumor volume doubling time of ~2 days, and a median time to euthanasia criteria (2000 mm3) of ~11 days. Bioanalysis of tumor-infiltrating lymphocyte (TIL) composition via flow cytometry confirms that the RM-1 tumor model has characteristics of a nonimmunogenic or a “cool” tumor. CD4+ T cell and CD8+ T cell populations ranged from 0.7 to 1.9% of the CD45+ cells. Comparatively, G-MDSC and M-MDSC populations were much higher at 8.3 and 63.8% of CD45+ cells. This type of TIL profile is ideal for combination therapies, providing a clear opportunity to turn a “cool” tumor “warm” and therefore potentially more responsive to treatment. To further characterize the RM-1 model, we evaluated anti-mPD-1, anti-mPD-L1, and anti-mCTLA-4. As expected, based on the TIL profile, single agent treatment with checkpoint inhibitors produced minimal anticancer activity, with no tumor regressions, and Citation Format: Justin Snider, Derrik Germain, Patrick Allison, Alden Wong, Sylvie Kossodo. Model characterization and tumor immune profile assessment for syngeneic RM-1 murine prostate cancer in male C57BL/6 mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1664.

TPS9600 Background: Immune checkpoint inhibitors (ICIs) are approved for multiple malignancies, however, durable remission rates with ICI monotherapy remains low. Combined treatment with anti-CTLA-4 and anti-PD1 has shown higher response rates in several cancers but is associated with up to 60% grade 3/4 immune-related adverse events (irAEs) leading to frequent treatment discontinuation. The need for corticosteroids to control irAEs may further diminish anti-tumor activity. A multi-disciplinary approach using clinical, preclinical, and translational analyses implicated the IL-6/Th17 axis in both ICI-related autoimmunity and resistance. Further, preliminary data showed that targeting interleukin 6 (IL-6) could be an effective approach to reduce irAEs while maintaining and possibly boosting the antitumor immune response. Methods: We are conducting a phase II, open-label, single center study to evaluate the use of combination treatment with tocilizumab (toci; anti-IL6), ipilimumab (ipi; anti-CTLA4) and nivolumab (nivo; anti-PD1) as a front-line therapy for patients (pts) with treatment-naïve advanced cutaneous melanoma (cohort 1), urothelial carcinoma (cohort 2), and EGFR mutant non-small cell lung cancer after tyrosine kinase inhibitors failure (cohort 3) (NCT04940299). Ten pts per disease site will be enrolled, plus an additional 25 melanoma pts in an expansion cohort. Key inclusion criteria are age ≥18 years (yrs) and histologically confirmed locally advanced or metastatic disease, with specific eligibility criteria defined for each cohort. Patients with interstitial lung diseases, autoimmune diseases, infection, or conditions requiring immunosuppressive therapies are not eligible, but stable asymptomatic brain mets are allowed. Ipi/Nivo dosing is as per approved disease indications: in cohort 1 &2, ipi 3 mg/kg + nivo 1 mg/kg is administered intravenously (IV) every 3 weeks (wks) for 4 doses then nivo 480 mg/4 wks up to 2 yrs. In cohort 3, IV ipi 1 mg/kg/6 wks + nivo 3 mg/kg/2 wks is administered up to 2 yrs. In all 3 cohorts, subcutaneous (SQ) toci 162 mg/2wks is administered up to 12 wks. Imaging is every 12 wks up to 2 yrs or until dose-limiting toxicities or progression. The primary outcome is safety/tolerability of the triple therapy. The secondary outcomes are antitumor efficacy and overall survival. Additionally, tumor and blood samples are being collected for longitudinal immune analysis, including gene expression and multiplex histochemistry to identify predictive biomarkers of response, resistance, and toxicity. The trial opened in October 2021 and has enrolled 14 patients to date. Clinical trial information: NCT04940299.

2511 Background: While ICB has significantly improved clinical outcomes across several cancer types, only 15-20% of patients develop a durable response. Thus, novel and targetable biomarkers are needed. There is increased appreciation of the role of the gut microbiome, and TLS and B-cells in the TME in response to ICB. Here, we investigate the association between these two determinants of response in patient specimens from three randomized phase 2 neoadjuvant ICB trials of nivolumab +/- ipilimumab (melanoma (MEL; NCT02519322; n=23), non-small-cell lung cancer (NSCLC; NCT03158129; n=31), sarcoma (SARC; NCT02301039; n=17). Methods: Patients were categorized as responders (R) or non-responders (NR) based on major pathologic response, as defined in each histotype (MEL and NSCLC viable tumor ≤10%; SARC hyalinization>30%). Baseline fecal samples were profiled via 16S rRNA gene sequencing from all three cohorts to assess the composition of patient gut microbiomes. Transcriptional profiles of biopsies collected pre-ICB for MEL and SARC, and post-ICB for MEL, SARC, and NSCLC were used to assess TLS (CXCL13, CCL18, CCL19, CCL21) and B-cell (PAX5, CD79B, CR2, MS4A1) signatures in the TME, by calculated mean values of normalized gene expressions. Comparison between samples were carried out using the Wilcoxon signed-rank test. Results: There were 21 R overall (NSCLC n=9; MEL n=9; SARC n=3). Despite significant differences in alpha and beta diversity across cohorts, relative abundance of Ruminococcus was significantly higher in R (p=0.003; NSCLC p

We investigate the use of parabolic equation (PE) methods for solving radio-wave propagation in polar ice. PE methods provide an approximate solution to Maxwell's equations, in contrast to full-field solutions such as finite-difference-time-domain (FDTD) methods, yet provide a more complete model of propagation than simple geometric ray-tracing (RT) methods that are the current state of the art for simulating in-ice radio detection of neutrino-induced cascades. PEs are more computationally efficient than FDTD methods, and more flexible than RT methods, allowing for the inclusion of diffractive effects and modeling of propagation in regions that cannot be modeled with geometric methods. We present a new PE approximation suited to the in-ice case. We conclude that current ray-tracing methods may be too simplistic in their treatment of ice properties, and their continued use could overestimate experimental sensitivity for in-ice neutrino detection experiments. We discuss the implications for current in-ice Askaryan-type detectors and for the upcoming Radar Echo Telescope, two families of experiments for which these results are most relevant. We suggest that PE methods be investigated further for in-ice radio applications., SCOPUS: ar.j, info:eu-repo/semantics/published

The Pierre Auger Observatory is designed to study cosmic rays of the highest energies ($>10^{19}$ eV). The ground array of the Observatory will consist of 1600 water Cherenkov detectors deployed over 3000 km^2. The remoteness and large number of detectors require a robust, automatic self-calibration procedure. It relies on the measurement of the average charge collected by a photomultiplier tube from the Cherenkov light produced by a vertical and central through-going muon determined to 5 - 10% at the detector via a novel rate-based technique and to 3% precision through analysis of histograms of the charge distribution. The parameters needed for the calibration are measured every minute, allowing for an accurate determination of the signals recorded from extensive air showers produced by primary cosmic rays. The method also enables stable and uniform triggering conditions to be achieved., 8 pages, 6 figures

The Radar Echo Telescope for Cosmic Rays (RET-CR) is a pathfinder experiment for the Radar Echo Telescope for Neutrinos (RET-N), a next-generation in-ice detection experiment for ultra high energy neutrinos. RET-CR will serve as the testbed for the radar echo method to probe high-energy particle cascades in nature, whereby a transmitted radio signal is reflected from the ionization left in its wake. This method, recently validated at SLAC experiment T576, shows promising preliminary sensitivity to neutrino-induced cascades above the energy range of optical detectors like IceCube. RET-CR intends to use an in-nature test beam: the dense, in-ice cascade produced when the air shower of an ultra high energy cosmic ray impacts a high-elevation ice sheet. This in-ice cascade, orders of magnitude more dense than the in-air shower that preceded it, is similar in profile and density to the expected cascade from a neutrino-induced cascade deep in the ice. RET-CR will be triggered using surface scintillator technology and will be used to develop, test, and deploy the hardware, firmware, and software needed for the eventual RET-N. We present the strategy, status, and design sensitivity of RET-CR, and discuss its application to eventual neutrino detection.

The SLAC T-576 beam test experiment showed the feasibility of the radar detection technique to probe high-energy particle cascades in dense media. Corresponding particle-level simulations indicate that the radar method has very promising sensitivity to probe the $>$PeV cosmic neutrino flux. As such, it is crucial to demonstrate the in-situ feasibility of the radar echo method, which is the main goal of the current RET-CR experiment. Although the final goal of the Radar Echo Telescope is to detect cosmic neutrinos, we seek a proof of principle using cosmic-ray air showers penetrating the (high-altitude) Antarctic ice sheet. When an UHECR particle cascade propagates into a high-elevation ice sheet, it produces a dense in-ice cascade of charged particles which can reflect incoming radio waves. Using a surface cosmic-ray detector, the energy and direction of the UHECR can be reconstructed, and as such this constitutes a nearly ideal in-situ test beam to provide the proof of principle for the radar echo technique. RET-CR will consist of a transmitter array, receiver antennas and a surface scintillator plate array. Here we present the simulation efforts for RET-CR performed to optimise the surface array layout and triggering system, which affords an estimate of the expected event rate.

The Radar Echo Telescope for Cosmic Rays (RET-CR) is a recently initiated experiment designed to detect the englacial cascade of a cosmic-ray initiated air shower via in-ice radar, toward the goal of a full-scale, next-generation experiment to detect ultra high energy neutrinos in polar ice. For cosmic rays with a primary energy greater than 10 PeV, roughly 10% of an air-shower's energy reaches the surface of a high elevation ice-sheet ($\gtrsim$2 km) concentrated into a radius of roughly 10 cm. This penetrating shower core creates an in-ice cascade many orders of magnitude more dense than the preceding in-air cascade. This dense cascade can be detected via the radar echo technique, where transmitted radio is reflected from the ionization deposit left in the wake of the cascade. RET-CR will test the radar echo method in nature, with the in-ice cascade of a cosmic-ray initiated air-shower serving as a test beam. We present the projected event rate and sensitivity based upon a three part simulation using CORSIKA, GEANT4, and RadioScatter. RET-CR expects $\sim$1 radar echo event per day.

The Askaryan Radio Array (ARA) is an ultra-high energy (UHE, $>10^{17}$ eV) neutrino detector designed to observe neutrinos by searching for the radio waves emitted by the relativistic products of neutrino-nucleon interactions in Antarctic ice. In this paper, we present constraints on the diffuse flux of ultra-high energy neutrinos between $10^{16}-10^{21}$ eV resulting from a search for neutrinos in two complementary analyses, both analyzing four years of data (2013-2016) from the two deep stations (A2, A3) operating at that time. We place a 90 % CL upper limit on the diffuse all flavor neutrino flux at $10^{18}$ eV of $EF(E)=5.6\times10^{-16}$ $\textrm{cm}^{-2}$$\textrm{s}^{-1}$$\textrm{sr}^{-1}$. This analysis includes four times the exposure of the previous ARA result, and represents approximately 1/5 the exposure expected from operating ARA until the end of 2022., 12 pages, 7 figures; Accepted to PRD

The observation of electromagnetic radiation from radio to $\gamma$-ray wavelengths has provided a wealth of information about the universe. However, at PeV (10$^{15}$ eV) energies and above, most of the universe is impenetrable to photons. New messengers, namely cosmic neutrinos, are needed to explore the most extreme environments of the universe where black holes, neutron stars, and stellar explosions transform gravitational energy into non-thermal cosmic rays. The discovery of cosmic neutrinos with IceCube has opened this new window on the universe. In this white paper, we present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the universe at the highest energies. IceCube-Gen2 is designed to: 1) Resolve the high-energy neutrino sky from TeV to EeV energies; 2) Investigate cosmic particle acceleration through multi-messenger observations; 3) Reveal the sources and propagation of the highest energy particles in the universe; 4) Probe fundamental physics with high-energy neutrinos. IceCube-Gen2 will increase the annual rate of observed cosmic neutrinos by a factor of ten compared to IceCube, and will be able to detect sources five times fainter than its predecessor. Furthermore, through the addition of a radio array, IceCube-Gen2 will extend the energy range by several orders of magnitude compared to IceCube. Construction will take 8 years and cost about \$350M. The goal is to have IceCube-Gen2 fully operational by 2033. IceCube-Gen2 will play an essential role in shaping the new era of multi-messenger astronomy, fundamentally advancing our knowledge of the high-energy universe. This challenging mission can be fully addressed only in concert with the new survey instruments across the electromagnetic spectrum and gravitational wave detectors which will be available in the coming years., Comment: 56 pages, 29 figures

The RET-N project aims to detect > 10 PeV neutrino-initiated cascades in ice using the radar echo technique. This will be a novel way of detecting cosmic neutrinos that will complement current approaches by other experiments. Here we discuss details of detector optimisation studies for the RET-N pathfinder and prototyping project. Furthermore, we present the modelling efforts to predict the radar signal from an ultra high energy neutrino or cosmic ray induced particle cascade.

BackgroundIntegrin αvβ8 activates TGFβ in immune cells. αvβ8 inhibitors have been shown to potentiate immune checkpoint blockade (ICB) in preclinical models [1]. Radioimmunotherapy (RIT) induces immunogenic cell death and antigen presentation, however it concurrently activates immunosuppressive pathways. Interestingly, αvβ8 immunosuppressive activity was implicated in radiotherapy resistance [2]. We have explored whether antagonizing αvβ8 overcomes the suppressive effect of TGFβ and restores anti-tumor immunity in advanced ICB and RIT resistant tumors.MethodsEfficacy was evaluated after combination treatment with low dose radiation, αvβ8 (clone C6D4) and PD-1 (clone J43) mAb in an advanced CT26 colon cancer syngeneic mouse model. Mice were treated at tumor volume of >120 mm3 and euthanized at 2,000 mm3. Flow cytometry and transcriptomic analysis were used to assess the mechanism of action. Tumor volumes are presented as mean±SEM. Statistics were performed by one-way ANOVA, or log-rank test. Bone marrow derived dendritic cell (BMdDC) cultures were isolated from C57BL/6 mice.ResultsCell death, including radiation-induced apoptosis, induced immunoregulatory and maturation program in a population of ex vivo cultured BMdDC, recently described as mregDC/DC3 [3,4]. mregDC/DC3 signature was associated with increased αvβ8 expression, suggesting a role of this integrin in inducing an immunosuppressive phenotype.A CT26 model was established to mimic the progression of late-stage tumors and was unresponsive to radiation, ICB and RIT. In CT26 implanted mice, αvβ8 is expressed on tumor stoma, and is not detectable on cancer cells. Addition of αvβ8 mAb to RIT markedly increased tumor regression (P=0.0067) and survival (PAbstract 595 Figure 1Complete response (CR) with improved survival when αvβ8 inhibition is added to RIT in CT26 syngeneic model of colorectal cancer in an advanced, ICB and RIT unresponsive stage. (A) Effect of combination therapy with low dose radiation (small animal radiation research platform (SARRP) at 5 Gray (Gy) on the day of staging (day 10)), PD-1 mAb (10 mg/kg twice weekly for 2 weeks) and αvβ8 mAb (7 mg/kg three times weekly for 3 weeks) measured by tumor burden. 5Gy+PD-1 and 5Gy+αvβ8 has a minimal effect on tumor growth inhibition showing slight improvement relative to radiation alone (5Gy+IgG). Addition of αvβ8 antagonism (5Gy+αvβ8+PD-1) improves anti-tumor responses leading to CR in 8 of 10 mice. (B) Kaplan-Meier Curve presenting time to progression. 5Gy+IgG improved survival over monotherapy with either αvβ8 or PD1 mAb. 5Gy+αvβ8+PD-1 resulted in a profound improvement of the survival over all other treatment conditionsConclusionsInhibition of αvβ8 in combination with RIT eradicated an advanced tumor, unresponsive to the respective monotherapies or conventional RIT. The anti-tumor effect was driven by enhancement of adaptive immunity, improvement of DC function and reduced tumor tolerance. These data provide evidence that αvβ8 inhibition enhances RIT and may be effective against ICB refractory tumors.ReferencesReszka-Blanco NJ,Yadav V, Krumpoch M, Cappellucci L, Cui D, Dowling JE, et al., Inhibition of integrin αvβ8 enhances immune checkpoint induced anti-tumor immunity by acting across immunologic synapse in syngeneic models of breast cancer. AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1559.Jin S, Lee WC, Aust D, Pilarsky C, Cordes N, β8 integrin mediates pancreatic cancer cell radiochemoresistance. Mol Cancer Res. 2019; 17(10): 2126–2138.Maier B, Leader AM, Chen ST, Tung N, Chang C, LeBerichel J, et al., A conserved dendritic-cell regulatory program limits antitumour immunity. Nature. 2020; 580 (7802): 257–262.Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S, Piot C, Engblom C, et al., Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity. 2018; 49(6): 1148–1161.Dodagatta-Marri E, Ma H-Y, Liang B, Li J, Meyer DS, Chen S-Y, et al., Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy. Cell Report. 2021; 36(1): 109309Ethics ApprovalAll animal work was approved by the site Institutional Animal Care and Use Committee and was performed in conformance with the Guide for the Care and Use of Laboratory Animals within an AAALAC-accredited program. Humane euthanasia criteria were predetermined on the basis of body weight and defined clinical observations.

The Payload for Ultrahigh Energy Observations (PUEO) long-duration balloon experiment is designed to have world-leading sensitivity to ultrahigh-energy neutrinos at energies above 1 EeV. Probing this energy region is essential for understanding the extreme-energy universe at all distance scales. PUEO leverages experience from and supersedes the successful Antarctic Impulsive Transient Antenna (ANITA) program, with an improved design that drastically improves sensitivity by more than an order of magnitude at energies below 30 EeV. PUEO will either make the first significant detection of or set the best limits on ultrahigh-energy neutrino fluxes., Comment: 40 pages, 17 figures. Version accepted to JINST

Colorectal cancer (CRC) is a major contributor to the whole of cancer as a disease, representing 10% of all cases of cancer. Recent clinical studies and FDA approvals demonstrate strong possibilities for the future of immunotherapy in the treatment of CRC. Highly translational preclinical models of the disease are required to assess the effectiveness of novel immuno-oncology agents. The CT26.WT murine colon carcinoma model is a widely used syngeneic tumor model to evaluate the preclinical efficacy of immuno-oncology agents. Subcutaneous tumor models are limited in translatability compared to the orthotopic implant site including differential stromal interactions, immune cell infiltrate, and response to immunotherapy. We present the development of a robust murine orthotopic colon tumor model (CT26.WT-luc) assessed by bioluminescence imaging (BLI) and assessed for response to common checkpoint targets. All animal work was performed in an AAALAC accredited facility, in alignment with applicable animal welfare regulations and with predetermined humane euthanasia criteria on all studies. Subcutaneous CT26.WT-luc tumors were dissected into fragments and grafted onto the cecum of naïve Balb/c mice. Mice were subjected to BLI twice weekly for four weeks for longitudinal monitoring of tumor growth. The tumor engraftment rate was 95% based on BLI and necropsy, no spontaneous regressions were observed. The BLI derived tumor volume doubling time was 1.5 days and the median time on study was 21 days. Common clinical observations associated with disease progression were abdominal distension due to tumor growth and bodyweight gain. Necropsy revealed large primary masses attached to the cecum with large vascular involvement, and small nodules on the liver and abdominal wall. To assess the model response to immunotherapy, Balb/c mice bearing orthotopic CT26.WT-luc tumors were treated by intraperitoneal administration of 10mg/kg isotype control, anti-PD-L1, anti-CTLA-4 or anti-PD-1 twice weekly for two weeks (Bio X Cell). Administration of anti-PD-L1 resulted in one complete regression. Anti-CTLA-4 treatment resulted in a day 23 ΔT/ΔC of 0.1% and five partial regressions with no visibly detectable disease at necropsy. Administration of anti-PD-1 did not result in regressions or tumor free survivors. Administration of either anti-PD-L1 or anti-CTLA-4 provided an increase of life span over isotype control of 13 and 24 days, respectively. Terminal necropsy revealed no evidence of tumors or other lesions in 1 out of 8 animals administered anti-PD-L1, and 5 out of 8 animals administered anti-CTLA-4. This model represents a powerful tool with translational potential for assessing the efficacy of novel immune modulating agents with the possibility of combination therapy. Assessment of tumor response, cell and molecular differences between subcutaneous and orthotopic CT26.WT-luc tumors is ongoing. Citation Format: Patrick Allison, Derrik Germain, Meredith Baugher, Maryland Franklin. CT26.WT-luc orthotopic syngeneic tumor model of colon cancer: development and immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2926.

We report on a search for ultra-high-energy (UHE) neutrinos from gamma-ray bursts (GRBs) in the data set collected by the Testbed station of the Askaryan Radio Array (ARA) in 2011 and 2012. From 57 selected GRBs, we observed no events that survive our cuts, which is consistent with 0.12 expected background events. Using NeuCosmA as a numerical GRB reference emission model, we estimate upper limits on the prompt UHE GRB neutrino fluence and quasi-diffuse flux from $10^{7}$ to $10^{10}$ GeV. This is the first limit on the prompt UHE GRB neutrino quasi-diffuse flux above $10^{7}$ GeV., Comment: 14 pages, 8 figures, Published in Astroparticle Physics Journal

A hydrophobic, highly transparent silica aerogel with a refractive index of $\sim $1.15 was developed using sol–gel polymerization, pin drying, and supercritical carbon dioxide solvent extraction technologies. A total of 96 monolithic tiles with dimensions of 11 cm $\times $ 11 cm $\times $ 1 cm were mass produced with a high crack-free yield for use as Cherenkov radiators to be installed in the proximity-focusing ring-imaging Cherenkov (RICH) detector. The RICH detector, containing 36 aerogel tiles, will be installed in the High Energy Light Isotope eXperiment (HELIX) spectrometer and used to measure the velocity of cosmic-ray particles. HELIX is a balloon-borne experimental program designed to measure the chemical and isotopic abundances of light cosmic-ray nuclei. A water-jet cut test of the aerogel tiles and a gluing test of the trimmed tiles with dimensions of 10 cm $\times $ 10 cm $\times $ 1 cm in an aluminum frame were successful in the context of integration into the radiator module.

HELIX (High Energy Light Isotope eXperiment) is a balloon-borne experiment designed to measure the chemical and isotopic abundances of light cosmic ray nuclei. Detailed measurements by HELIX, especially of $^{10}$Be from 0.2 GeV/n to beyond 3 GeV/n, will provide an essential set of data for the study of propagation processes of the cosmic rays. HELIX consists of a 1 Tesla superconducting magnet with a high-resolution gas tracking system, time-of-flight detector, and a ring-imaging Cherenkov detector. The instrument is scheduled to have a long-duration balloon flight out of McMurdo Station during NASA's 2020/21 Antarctic balloon campaign. Here, we discuss the scientific goals and the design of the experiment, and report on its current status.

HELIX (High Energy Light Isotope eXperiment) is a balloon-borne experiment designed to measure the chemical and isotopic abundances of light cosmic ray nuclei, especially the $^{\textrm{10}}\textrm{Be}/^{\textrm{9}}\textrm{Be}$ ratio over the energy range from 0.2 GeV/n to beyond 3 GeV/n. This is a key measurement for constraining cosmic-ray propagation models. The detector is a mass spectrometer, which is built around a 1 Tesla superconducting magnet and a high-resolution tracking system to determine particle rigidity. Time-of-flight counters and a ring-imaging Cherenkov detector (RICH) are used to measure velocities. The proximity-focused RICH consists of a radiator made of aerogel tiles (refractive index approximately 1.15) and a detector plane of silicon photomultipliers. For discrimination of the $^{\textrm{9}}\textrm{Be}$ and $^{\textrm{10}}\textrm{Be}$ isotopes at high energy, the refractive index of the aerogel must be known to a precision of 0.07%. Given the manufacturing tolerances in the production process, the index must be mapped over the lateral extent of aerogel tiles on a fine grid. In this contribution, we describe and show initial results from procedures developed for this task. These include laser-deflection and electron-beam measurements.

Recently, the ANITA collaboration reported on two upward-going extensive air shower events consistent with a primary particle that emerges from the surface of the ice. These events may be of $\nu_\tau$ origin, in which the neutrino interacts within the Earth to produce a $\tau$ lepton that emerges from the Earth, decays in the atmosphere, and initiates an extensive air shower. In this paper we estimate an upper bound on the ANITA acceptance to a diffuse $\nu_\tau$ flux detected via $\tau$-lepton-induced air showers within the bounds of Standard Model (SM) uncertainties. By comparing this estimate with the acceptance of Pierre Auger Observatory and IceCube and assuming SM interactions, we conclude that a $\nu_\tau$ origin of these events would imply a neutrino flux at least two orders of magnitude above current bounds., Comment: 12 pages, 7 figures

The ANtarctic Impulsive Transient Antenna (ANITA) NASA long-duration balloon payload completed its fourth flight in December 2016, after 28 days of flight time. ANITA is sensitive to impulsive broadband radio emission from interactions of ultra-high-energy neutrinos in polar ice (Askaryan emission). We present the results of two separate blind analyses searching for signals from Askaryan emission in the data from the fourth flight of ANITA. The more sensitive analysis, with a better expected limit, has a background estimate of $0.64^{+0.69}_{-0.45}$ and an analysis efficiency of $82\pm2\%$. The second analysis has a background estimate of $0.34^{+0.66}_{-0.16}$ and an analysis efficiency of $71\pm6\%$. Each analysis found one event in the signal region, consistent with the background estimate for each analysis. The resulting limit further tightens the constraints on the diffuse flux of ultra-high-energy neutrinos at energies above $10^{19.5}$ eV., 11 pages, 7 figures

This paper reports the successful fabrication of silica aerogel Cherenkov radiators produced in the first batches from a 96-tile mass production performed using pin-drying technique in our laboratory. The aerogels are to be used in a ring-imaging Cherenkov detector in the spectrometer of a planned balloon-borne cosmic-ray observation program, HELIX (High Energy Light Isotope eXperiment). A total of 36 transparent, hydrophobic aerogel tiles with a high refractive index of 1.16 and dimensions of 10 cm $\times $ 10 cm $\times $ 1 cm will be chosen as the flight radiators. Thus far, 40 out of the 48 tiles fabricated were confirmed as having no tile cracking. In the first screening, 8 out of the first 16 tiles were accepted as flight-qualified candidates, based on basic optical measurement results. To fit the aerogel tiles into a radiator support structure, the trimming of previously manufactured prototype tiles using a water-jet cutting device was successful., Submitted to Nucl. Instrum. Methods Phys. Res. A (NIMA Proc. Special Issue: RICH 2018), 5 pages, 6 figures

We report the observation of radar echoes from the ionization trails of high-energy particle cascades. These data were taken at the SLAC National Accelerator Laboratory, where the full electron beam ($\sim$10$^9$ e$^-$ at $\sim$10 GeV/e$^-$) was directed into a plastic target to simulate an ultra high-energy neutrino interaction. This target was interrogated with radio waves, and coherent radio reflections from the cascades were detected, with properties consistent with theoretical expectations. This is the first definitive observation of radar echoes from high-energy particle cascades, which may lead to a viable neutrino detection technology for energies $\gtrsim 10^{16}$ eV., Comment: 6 pages, 4 figures

A Monte Carlo simulation program for the radio detection of Ultra High Energy (UHE) neutrino interactions in the Antarctic ice as viewed by the Antarctic Impulsive Transient Antenna (ANITA) is described in this article. The program, icemc, provides an input spectrum of UHE neutrinos, the parametrization of the Askaryan radiation generated by their interaction in the ice, and the propagation of the radiation through ice and air to a simulated model of the third and fourth ANITA flights. This paper provides an overview of the icemc simulation, descriptions of the physics models used and of the ANITA electronics processing chain, data/simulation comparisons to validate the predicted performance, and a summary of the impact of published results.

We report on analysis of englacial radio-frequency (RF) pulser data received over horizontal baselines of 1--5 km, based on broadcasts from two sets of transmitters deployed to depths of up to 1500 meters at the South Pole. First, we analyze data collected usingtwo RF bicone transmitters 1400 meters below the ice surface, and frozen into boreholes drilled for the IceCube experiment in 2011. Additionally, in Dec., 2018, a fat-dipole antenna, fed by one of three high-voltage (~1 kV), fast (~(1-5 ns)) signal generators was lowered into the 1700-m deep icehole drilled for the South Pole Ice Core Experiment (SPICE), approximately 3 km from the geographic South Pole. Signals from transmitters were recorded on the five englacial multi-receiver ARA stations, with receiver depths between 60--200 m. We confirm the long, >1 km RF electric field attenuation length, test our observed signal arrival timing distributions against models, and measure birefringent asymmetries at the 0.15% level.

The biology of bone healing is a rapidly developing science. Advances in transgenic and gene-targeted mice have enabled tissue and cell-specific investigations of skeletal regeneration. As an example, only recently has it been recognized that chondrocytes convert to osteoblasts during healing bone, and only several years prior, seminal publications reported definitively that the primary tissues contributing bone forming cells during regeneration were the periosteum and endosteum. While genetically modified animals offer incredible insights into the temporal and spatial importance of various gene products, the complexity and rapidity of healing-coupled with the heterogeneity of animal models-renders studies of regenerative biology challenging. Herein, cells that play a key role in bone healing will be reviewed and extracellular mediators regulating their behavior discussed. We will focus on recent studies that explore novel roles of inflammation in bone healing, and the origins and fates of various cells in the fracture environment. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

We report on an upward traveling, radio-detected cosmic-ray-like impulsive event with characteristics closely matching an extensive air shower. This event, observed in the third flight of the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload, is consistent with a similar event reported in a previous flight. These events may be produced by the atmospheric decay of an upward-propagating $\tau$-lepton produced by a $\nu_{\tau}$ interaction, although their relatively steep arrival angles create tension with the standard model (SM) neutrino cross section. Each of the two events have $a~posteriori$ background estimates of $\lesssim 10^{-2}$ events. If these are generated by $\tau$-lepton decay, then either the charged-current $\nu_{\tau}$ cross section is suppressed at EeV energies, or the events arise at moments when the peak flux of a transient neutrino source was much larger than the typical expected cosmogenic background neutrinos., Comment: 5 pages, 4 figures. Supplemental material available from corresponding author by request

The LAB4D is a new application-specific integrated circuit (ASIC) of the Large Analog Bandwidth Recorder and Digitizer with Ordered Readout (LABRADOR) family, for use in direct wideband radio frequency digitization such as is used in ultrahigh energy neutrino and cosmic ray astrophysics . The LAB4D is a single channel switched-capacitor array (SCA) 12-bit sampler with integrated analog-to-digital converters (ADC), developed in the TSMC 0.25 µm process. The LAB4D, operating at 3 . 2 GSa ∕ s , contains 4096 total samples arranged in 32 windows, for a total record length of 1280 ns. The 3 dB bandwidth is approximately 1.3 GHz, with a directly-coupled 50 Ω input. This represents a factor of 16 increase in the sample depth and an increase in analog bandwidth in comparison to the previous generation (LAB3) digitizer. Individually addressable windows allow for sampling and digitization to occur simultaneously, leading to nearly dead time-free kHz readout rates. All biases and current references are generated via internal digital-to-analog converters (DACs), resulting in a digitizer that requires minimal support circuitry. In addition, the LAB4D contains sample cell timebase trimming capabilities, reducing the intrinsic sample-to-sample time variance to less than 5 ps, an improvement of about 80%. This feature allows the LAB4D to be used in precision timing applications and reduces post-hoc calibration requirements.

The Antarctic Impulsive Transient Antenna (ANITA), a NASA long-duration balloon payload, searches for radio emission from interactions of ultra-high-energy neutrinos in polar ice. The third flight of ANITA (ANITA-III) was launched in December 2014 and completed a 22-day flight. We present the results of three analyses searching for Askaryan radio emission of neutrino origin. In the most sensitive of the analyses, we find one event in the signal region on an expected a priori background of $0.7^{+0.5}_{-0.3}$. Though consistent with the background estimate, the candidate event remains compatible with a neutrino hypothesis even after additional post-unblinding scrutiny., Comment: 15 pages, 15 figures, Accepted to PRD

The balloon-borne HiCal radio-frequency (RF) transmitter, in concert with the ANITA radio-frequency receiver array, is designed to measure the Antarctic surface reflectivity in the RF wavelength regime. The amplitude of surface-reflected transmissions from HiCal, registered as triggered events by ANITA, can be compared with the direct transmissions preceding them by O(10) microseconds, to infer the surface power reflection coefficient $\cal{R}$. The first HiCal mission (HiCal-1, Jan. 2015) yielded a sample of 100 such pairs, resulting in estimates of $\cal{R}$ at highly-glancing angles (i.e., zenith angles approaching $90^\circ$), with measured reflectivity for those events which exceeded extant calculations. The HiCal-2 experiment, flying from Dec., 2016-Jan., 2017, provided an improvement by nearly two orders of magnitude in our event statistics, allowing a considerably more precise mapping of the reflectivity over a wider range of incidence angles. We find general agreement between the HiCal-2 reflectivity results and those obtained with the earlier HiCal-1 mission, as well as estimates from Solar reflections in the radio-frequency regime. In parallel, our calculations of expected reflectivity have matured; herein, we use a plane-wave expansion to estimate the reflectivity R from both a flat, smooth surface (and, in so doing, recover the Fresnel reflectivity equations) and also a curved surface. Multiplying our flat-smooth reflectivity by improved Earth curvature and surface roughness corrections now provides significantly better agreement between theory and the HiCal 2a/2b measurements., Comment: submitted to Astropart. Phys

Ultra-high energy neutrinos are detectable through impulsive radio signals generated through interactions in dense media, such as ice. Subsurface in-ice radio arrays are a promising way to advance the observation and measurement of astrophysical high-energy neutrinos with energies above those discovered by the IceCube detector ($\geq$1 PeV) as well as cosmogenic neutrinos created in the GZK process ($\geq$100 PeV). Here we describe the $\textit{NuPhase}$ detector, which is a compact receiving array of low-gain antennas deployed 185 m deep in glacial ice near the South Pole. Signals from the antennas are digitized and coherently summed into multiple beams to form a low-threshold interferometric phased array trigger for radio impulses. The NuPhase detector was installed at an Askaryan Radio Array (ARA) station during the 2017/18 Austral summer season. $\textit{In situ}$ measurements with an impulsive, point-source calibration instrument show a 50% trigger efficiency on impulses with voltage signal-to-noise ratios (SNR) of $\le$2.0, a factor of $\sim$1.8 improvement in SNR over the standard ARA combinatoric trigger. Hardware-level simulations, validated with $\textit{in situ}$ measurements, predict a trigger threshold of an SNR as low as 1.6 for neutrino interactions that are in the far field of the array. With the already-achieved NuPhase trigger performance included in ARASim, a detector simulation for the ARA experiment, we find the trigger-level effective detector volume is increased by a factor of 1.8 at neutrino energies between 10 and 100 PeV compared to the currently used ARA combinatoric trigger. We also discuss an achievable near term path toward lowering the trigger threshold further to an SNR of 1.0, which would increase the effective single-station volume by more than a factor of 3 in the same range of neutrino energies., Comment: 19 pages, 19 figures, submitted to Nuclear Instruments and Methods in Physics Research A

During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. This process requires epithelial to mesenchymal transition (EMT) and directed cellular invasion. The Type III Transforming Growth Factor-beta Receptor (TGFβR3) is required for epicardial cell invasion and coronary vessel development. Using primary epicardial cells derived from Tgfbr3(+/+) and Tgfbr3(-/-) mouse embryos, high-molecular weight hyaluronan (HMWHA) stimulated cellular invasion and filamentous (f-actin) polymerization are detected in Tgfbr3(+/+) cells, but not in Tgfbr3(-/-) cells. Furthermore, HMWHA-stimulated cellular invasion and f-actin polymerization in Tgfbr3(+/+) epicardial cells are dependent on Src kinase. Src activation in HMWHA-stimulated Tgfbr3(-/-) epicardial cells is not detected in response to HMWHA. RhoA and Rac1 also fail to activate in response to HMWHA in Tgfbr3(-/-) cells. These events coincide with defective f-actin formation and deficient cellular invasion. Finally, a T841A activating substitution in TGFβR3 drives ligand-independent Src activation. Collectively, these data define a TGFβR3-Src-RhoA/Rac1 pathway that is essential for hyaluronan-directed cell invasion in epicardial cells.

We describe herein a measurement of the Antarctic surface “roughness” performed by the balloon-borne ANITA (Antarctic Impulsive Transient Antenna) experiment. Originally purposed for cosmic ray astrophysics, the radio frequency (RF) receiver ANITA gondola, from its 38 km altitude vantage point, can scan a disk of snow surface 600 km in radius. The primary purpose of ANITA is to detect RF emissions from cosmic rays incident on Antarctica, such as neutrinos which penetrate through the atmosphere and interact within the ice, resulting in signal directed upward which then refracts at the ice-air interface and up and out to ANITA, or high-energy nuclei (most likely irons or protons), which interact in the upper atmosphere (at altitudes below ANITA) and produce a spray of down-coming RF which reflects off the snow surface and back up to the gondola. The energy of such high-energy nuclei can be inferred from the observed reflected signal only if the surface reflectivity is known. We describe herein an attempt to quantify the Antarctic surface reflectivity, using the Sun as a constant, unpolarized RF source. We find that the reflectivity of the surface generally follows the expectations from the Fresnel equations, lending support to the use of those equations to give an overall correction factor to calculate cosmic ray energies for all locations in Antarctica. The analysis described below is based on ANITA-II data. After launching from McMurdo Station in December 2008, ANITA-II was aloft for a period of 31 days with a typical instantaneous duty cycle exceeding 95%.

We are developing a ground-based radio interferometric phased array for radio detection of high energy neutrinos, in an effort to lower the energy threshold of radio detection experiments while increasing the effective volume at high energies. The radio detection technique looks for Askaryan emission from neutrinos interacting in large volumes of glacial ice. The principle behind the phased array technique is coherent summing of the broadband, impulsive Askaryan signal from multiple antenna channels, increasing the signal-to-noise ratio for triggering on weak signals. We first discuss simulations and validation measurements related to the phased array technique, including results from a preliminary Monte Carlo simulation, a demonstration of beamforming and measurements of thermal noise correlation in an anechoic chamber, and results from a trigger simulation. We then discuss the design and development of the first ground-based interferometric phased array trigger system, a 16-channel system that has been built and will be deployed as part of one Askaryan Radio Array (ARA) station in December 2017 at the South Pole.