The formation of the Earth remains an epoch with mysterious puzzles extending to our still incomplete understanding of the planet's potential origin and bulk composition. Direct confirmation of the Earth's internal heat engine was accomplished by the successful observation of geoneutrinos originating from uranium (U) and thorium (Th) progenies, manifestations of the planet's natural radioactivity dominated by potassium (40K) and the decay chains of uranium (238U) and thorium (232Th). This radiogenic energy output is critical to planetary dynamics and must be accurately measured for a complete understanding of the overall heat budget and thermal history of the Earth. Detecting geoneutrinos remains the only direct probe to do so and constitutes a challenging objective in modern neutrino physics. In particular, the intriguing potassium geoneutrinos have never been observed and thus far have been considered impractical to measure. We propose here a novel approach for potassium geoneutrino detection using the unique antimatter signature of antineutrinos to reduce the otherwise overwhelming backgrounds to observing this rarest signal. The proposed detection framework relies on the innovative LiquidO detection technique to enable positron (e+) identification and antineutrino interactions with ideal isotope targets identified here for the first time. We also provide the complete experimental methodology to yield the first potassium geoneutrino discovery.

The International Large Detector, ILD, is a detector concept for an experiment at a future high energy lepton collider. The detector has been optimised for precision physics in a range of energies from 90~GeV to about 1~TeV. ILD features a high precision, large volume combined silicon and gaseous tracking system, together with a high granularity calorimeter, all inside a central solenoidal magnetic field. The paradigm of particle flow has been the guiding principle of the design of ILD. ILD is based mostly on technologies which have been demonstrated by extensive research and test programs. The ILD concept is proposed both for linear and circular lepton collider, be it at CERN or elsewhere. The concept has been developed by a group of nearly 60 institutes from around the world, and offers a well developed and powerful environment for science and technology studies at lepton colliders. In this document, the required performance of the detector, the proposed implementation and the readiness of the different technologies needed for the implementation are discussed.

The determination of the direction of a stellar core collapse via its neutrino emission is crucial for the identification of the progenitor for a multimessenger follow-up. A highly effective method of reconstructing supernova directions within the Deep Underground Neutrino Experiment (DUNE) is introduced. The supernova neutrino pointing resolution is studied by simulating and reconstructing electron-neutrino charged-current absorption on Ar-40 and elastic scattering of neutrinos on electrons. Procedures to reconstruct individual interactions, including a newly developed technique called "brems flipping," as well as the burst direction from an ensemble of interactions are described. Performance of the burst direction reconstruction is evaluated for supernovae happening at a distance of 10 kpc for a specific supernova burst flux model. The pointing resolution is found to be 3.4 degrees at 68% coverage for a perfect interaction-channel classification and a fiducial mass of 40 kton, and 6.6 degrees for a 10 kton fiducial mass respectively. Assuming a 4% rate of charged-current interactions being misidentified as elastic scattering, DUNE's burst pointing resolution is found to be 4.3 degrees (8.7 degrees) at 68% coverage.

We present the characterization of a novel radiation detector based on an opaque water-based liquid scintillator. Opaque scintillators, also known as LiquidO, are made to be highly scattering, such that the scintillation light is effectively confined, and read out through wavelength-shifting fibers. The 1-liter, 32-channel prototype demonstrates the capability for both spectroscopy and topological reconstruction of point-like events. The design, construction, and evaluation of the detector are described, including modeling of the scintillation liquid optical properties and the detector's response to gamma rays of several energies. A mean position reconstruction error of 4.4 mm for 1.6 MeV-equivalent events and 7.4 mm for 0.8 MeV-equivalent events is demonstrated using a simple reconstruction approach analogous to center-of-mass.

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements, and provide comparisons to detector simulations.

Background: The HLA-B27 allele has been associated with spondyloarthritis (SpA); however, in the Colombian population it is present in only 40% of patients, and HLA-B15 is present in almost 25%. A polygenic mechanism has been proposed to explain the development of SpA. Endoplasmic reticulum aminopeptidase (ERAP) genes 1 and 2 have been implicated. Additionally, the cytokine profile is different in the SpA subtypes. These allowed two models of disease, one with HLA-B27 and axial presentation and a second with HLA-B15 and peripheral presentation. Objectives: The aim was to determine the association between ERAP polymorphisms, cytokine profile, and patients with HLA-B27 or HLA-B15 positive SpA. Methods: 168 SpA patients were evaluated based on ASAS criteria, and HLA typing was performed via PCR technique. The polymorphisms were determined by the RT-PCR technique using Roche® probes for ERAP1 rs27044, rs17482078, rs10050860, and rs30187. For ERAP2, the probes used were rs2910686, rs2248374 and rs2549782. Human Cytokine/Chemokine Magnetic Bead Panel kit from Millipore (Human Th17MAG-14 Px25K) (Merck) determined the cytokine serum concentration. All reagents were provided with the kit and were prepared according to the manufacturer’s recommendations.The allele and genotype frequencies polymorphisms were obtained by direct counting. In each group, the Hardy-Weinberg equilibrium was evaluated using the 2 test. The haplotypes were constructed and analyzed using Haploview v.4.2. Associations were assessed using odds ratio (OR). Stata v.17.0 program was used to analyze data. PCA used PRISMA 10 program. Results: 111 patients were HLA-B27, and 57 were HLA-B15. 63 (37.5%) were women, and 105 (62.5%) were men. In the association test we identified sixteen haplotypes, of which three associated significantly with protection (CCCCCAC, GTCCCAC, GTTTTAC; p<0.005) and one risk haplotype [GTCCTGC; 4.272(1.565-11.655), p<0.005] were described in Figure 1. Through the analysis of the Pearson Correlation Coefficient (PCC) and the Principal Component Analysis (PCA), we detected a profile of variables that characterize the HLA-B15 group, which were spinal pain, elderly, arthritis as first symptom in onset disease, more peripheral manifestations, polymorphism rs10050860, and rs30187, highest IL9, IL10, IL12, IL13, IL15, IL17f, IL21, IL22, IL23, IL28a, IL33, TNFβ, GM-CSF. The variables that characterized the HLA-B27 group were higher correlation with men, axial, lumbar pain, poor BASFI, BASDAI, polymorphism rs10050860 and rs30187, highest IL22, IL23, IL25, IL31, IL33 (Figure 2). Conclusion: In the population analyzed, we found a characteristic profile of SpA presentation that could be determined by the HLA-B15 or B27 allele, ERAP inheritance patterns, and cytokine concentrations. This could suggest the influence of ERAP on the profile of secreted cytokines in these patients and their clinical presentation. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.Figure 1Linkage disequilibrium map of the ERAP gene in patients with HLA-B15 y HLA-B27. Figure 2Pearson Correlation Coefficient (PCC) and Principal Component Analysis (PCA) of the HLA-B15 and HLA-B27 patient group.

Purpose/Objective(s)ADP-A2M4CD8 is an autologous CD4+ and CD8+ T-cell therapy under investigation for treatment of advanced cancers in human leukocyte antigen (HLA)-A*02–eligible participants. It expresses a genetically modified T-cell receptor (TCR) targeting melanoma-associated antigen A4 (MAGE-A4) and an additional CD8α co-receptor to increase functionality of CD4+ T cells. ADP-A2M4CD8 monotherapy has demonstrated an acceptable benefit-risk profile in the ongoing Phase 1 SURPASS trial (NCT04044859), with clinical responses in multiple tumor types in the late-line setting. As of November 23, 2022, in four SURPASS patients with head and neck (H&N) squamous cell carcinoma, best overall responses were three partial responses and one stable disease (median [range] duration of response, 8.7 [7.4–20.1] weeks) (Hong DS, et al. Presentation S152, AHNS 2023, Montreal, Canada). These results, along with data that suggest inhibition of immunosuppressive pathways may enhance ADP-A2M4CD8 anti-tumor activity (Kim PS, Ahmed R. Curr Opin Immunol. 2010;22:223; Gray KG, et al. Clin Cancer Res. 2020;26:6003), provided rationale for opening a new SURPASS cohort investigating safety and efficacy of first-line ADP-A2M4CD8 TCR T-cell therapy combined with pembrolizumab in patients with H&N cancers.Materials/MethodsThe dedicated H&N cohort will comprise ≤15 participants with newly metastatic or unresectable locally advanced H&N tumors with combined PD-L1 positive score ≥1 who are receiving pembrolizumab with or without chemotherapy as first-line standard-of-care therapy, with no evidence of disease progression before lymphodepletion. Key eligibility criteria include ≥30% of tumor cells expressing MAGE-A4 (≥2+ by immunohistochemistry); positivity for HLA-A*02:01, 02:02, 02:03, or 02:06 alleles; measurable disease per RECIST v1.1 before lymphodepletion; and ECOG performance status of 0 or 1. Participants will undergo leukapheresis, and collected T cells will be transduced with a lentiviral vector expressing the MAGE-A4-specific TCR and CD8α co-receptor and expanded ex vivo. Lymphodepletion chemotherapy consisting of cyclophosphamide 600 mg/m2/day for 3 days and fludarabine 30 mg/m2/day for 4 days is administered, followed by ADP-A2M4CD8 infusion (1–10 × 109 transduced T cells). Participants will then continue to receive pembrolizumab 400 mg every 6 weeks for ≤2 years, or unacceptable toxicity or disease progression. Primary and secondary objectives are to evaluate safety and anti-tumor activity, respectively.ResultsTBDConclusionIn a dedicated H&N cohort, participants will receive ADP-A2M4CD8 in combination with pembrolizumab in the first-line setting to evaluate the efficacy and safety of the combination. Study sponsor: Adaptimmune; writing/editing: Excel Scientific Solutions, funded by Adaptimmune.

ProtoDUNE Single-Phase (ProtoDUNE-SP) is a 770-ton liquid argon time projection chamber that operated in a hadron test beam at the CERN Neutrino Platform in 2018. We present a measurement of the total inelastic cross section of charged kaons on argon as a function of kaon energy using 6 and 7 GeV/$c$ beam momentum settings. The flux-weighted average of the extracted inelastic cross section at each beam momentum setting was measured to be 380$\pm$26 mbarns for the 6 GeV/$c$ setting and 379$\pm$35 mbarns for the 7 GeV/$c$ setting.

The Deep Underground Neutrino Experiment (DUNE) is a next generation experiment aimed to study neutrino oscillation. Its long-baseline configuration will exploit a Near Detector (ND) and a Far Detector (FD) located at a distance of similar to 1300 km. The FD will consist of four Liquid Argon Time Projection Chamber (LAr TPC) modules. A Photon Detection System (PDS) will be used to detect the scintillation light produced inside the detector after neutrino interactions. The PDS will be based on light collectors coupled to Silicon Photomultipliers (SiPMs). Different photosensor technologies have been proposed and produced in order to identify the best samples to fullfill the experiment requirements. In this paper, we present the procedure and results of a validation campaign for the Hole Wire Bonding (HWB) MPPCs samples produced by Hamamatsu Photonics K.K. (HPK) for the DUNE experiment, referring to them as 'SiPMs'. The protocol for a characterization at cryogenic temperature (77 K) is reported. We present the down-selection criteria and the results obtained during the selection campaign undertaken, along with a study of the main sources of noise of the SiPMs including the investigation of a newly observed phenomenon in this field.

The CMS detector, including its muon system, has been operating at the CERN LHC in increasingly challenging conditions for about 15 years. The muon detector was designed to provide excellent triggering and track reconstruction for muons produced in proton–proton collisons at an instantaneous luminosity ( ℒ ) of 1 × 10^34 cm ^-2 s ^-1 . During the Run 2 data-taking period (2015–2018), the LHC achieved an instantaneous luminosity of twice its design value, resulting in larger background rates and making the efficient detection of muons more difficult. While some backgrounds result from natural radioactivity, cosmic rays, and interactions of the circulating protons with residual gas in the beam pipe, the dominant source of background hits in the muon system arises from proton–proton interactions themselves. Charged hadrons leaving the calorimeters produce energy deposits in the muon chambers. In addition, high-energy particles interacting in the hadron calorimeter and forward shielding elements generate thermal neutrons, which leak out of the calorimeter and shielding structures, filling the CMS cavern. We describe the method used to measure the background rates in the various muon subsystems. These rates, in conjunction with simulations, can be used to estimate the expected backgrounds in the High-Luminosity LHC. This machine will run for at least 10 years starting in 2029 reaching an instantaneous luminosity of ℒ = 5 ×10^34 cm^-2 s^-1 and increasing ultimately to ℒ = 7.5 ×10^34 cm^-2 s^-1 . These background estimates have been a key ingredient for the planning and design of the muon detector upgrade.

The Photon Detection System (PDS) of the first DUNE far detector (FD1) is composed of 6000 photon detection units, named X-ARAPUCA. The detection of the prompt light pulse generated by the particle energy release in liquid argon (LAr) will complement and boost the DUNE Liquid Argon Time Projection Chamber (LArTPC). It will improve the non-beam events tagging and enable at low energies the trigger and the calorimetry of the supernova neutrinos. The X-ARAPUCA unit is an assembly of several components. Its Photon Detection Efficiency (PDE) depends both on the design of the assembly, on the grade of the individual components and finally on their coupling. The X-ARAPUCA PDE is one of the leading parameters for the Photon Detection System sensitivity, that in turn determines the sensitivity of the DUNE for the detection of core-collapse supernova within the galaxy and for nucleon decay searches. In this work we present the final assessment of the absolute PDE of the FD1 X-ARAPUCA baseline design, measured in two laboratories with independent methods and setups. One hundred sixty units of these X-ARAPUCA devices have been deployed in the NP04 facility at the CERN Neutrino Platform, the 1:20 scale FD1 prototype, and will be operated during the year 2024. The assessed value of the PDE is a key parameter both in the NP04 and in the DUNE analysis and reconstruction studies.

Abstract BACKGROUND ATP-dependent helicase (ATRX) loss-of-function mutations are a hallmark driver in IDH-mutated astrocytoma, and they are usually associated with the loss of P53 and the presence of the alternative lengthening of telomeres (ALT) phenotype. Inhibition of ataxia telangiectasia and Rad3-related (ATR), a key protein kinase involved in response to DNA damage, has shown preclinical synthetic lethality in ATRX mutated tumors, more specifically with ALT. Preclinical evidence also suggests that IDH mutant tumors show increased DNA damage and potential sensitization to ATR inhibition. MATERIAL AND METHODS Here we report a case series of 5 IDH mutant glioma patients who also harbored ATRX loss andP53 mutations enrolled in the biomarker-selected (ATRXX/DAXXmut) expansion cohort of the NCT04170153 study. We have summarized the clinical and pathological characteristics of the patients as well as the treatment duration, the PFS1/PFS2 ratio and the growth rate prior and after tuvusertib (ATR inhibitor) treatment given at its recommended dose for expansion (RDE): 180 mg QD, 2 weeks on/1 week off. RESULTS A total of 5 patients were included with an age range of 32-49 years. 3/5 were male. All of them had high-grade IDH mutant gliomas(G3-Astrocytoma) showing tumor enhancement on the baseline MR in all cases. All patients had received multi-modal treatment with surgery, radiotherapy, and systemic treatment with alkylating chemotherapy. Three patients had received 1 previous line of therapy, and 2 patients had received 3 previous lines of therapy. Treatment duration with tuvusertib was 0.5/ 1/ 2.5/ 18+/ 19+ months. No patient achieved a partial or complete response, but 2/5 patients experienced prolonged disease stabilization (>18 months), currently still on treatment. In those 2 cases, median growth rate (calculated as mm/year of change in the major axis of the target lesion) was 22 and 9 mm/year before treatment with tuvusertib but decreased to 1 mm and 2 mm/yearafter. PFS2/PFS1 in those two patients was 1.56 and 2.25, respectively. CONCLUSION While the number of patients is very limited, this is the first report showing preliminary signs of clinical activity of an ATR inhibitor in patients with recurrent IDH-mutant glioma in the clinical setting. The observed decrease in tumor growth rate associated with prolonged disease stabilization in treatment-refractory glioma warrants further investigation of tuvusertib in this indication. [MV1]All patients had molecular G3 IDH mutant astrocytoma, but one case has the diagnosis of G3 IDH mutant oligo-astrocytoma based on morphology [MV2]We can mention here that IDH inhibitors efficacy seems to be limited to low-grade, treatment naive non enhancing disease, where tuvusertib is active in high grade refractory tumors

AbstractThe CMS detector, including its muon system, has been operating at the CERN LHC in increasingly challenging conditions for about 15 years. The muon detector was designed to provide excellent triggering and track reconstruction for muons produced in proton–proton collisons at an instantaneous luminosity ($$\mathcal {L}$$ L ) of $$1 \times 10^{34}$$ 1 × 10 34 cm$$^{-2}$$ - 2 s$$^{-1}$$ - 1 . During the Run 2 data-taking period (2015–2018), the LHC achieved an instantaneous luminosity of twice its design value, resulting in larger background rates and making the efficient detection of muons more difficult. While some backgrounds result from natural radioactivity, cosmic rays, and interactions of the circulating protons with residual gas in the beam pipe, the dominant source of background hits in the muon system arises from proton–proton interactions themselves. Charged hadrons leaving the calorimeters produce energy deposits in the muon chambers. In addition, high-energy particles interacting in the hadron calorimeter and forward shielding elements generate thermal neutrons, which leak out of the calorimeter and shielding structures, filling the CMS cavern. We describe the method used to measure the background rates in the various muon subsystems. These rates, in conjunction with simulations, can be used to estimate the expected backgrounds in the High-Luminosity LHC. This machine will run for at least 10 years starting in 2029 reaching an instantaneous luminosity of $$\mathcal {L} = 5 \times \text {10}^\text {34}\,\text {cm}^\text {-2}\,\text {s}^\text {-1}$$ L = 5 × 10 34 cm -2 s -1 and increasing ultimately to $$\mathcal {L} = 7.5 \times \text {10}^\text {34}\,\text {cm}^\text {-2}\,\text {s}^\text {-1}$$ L = 7.5 × 10 34 cm -2 s -1 . These background estimates have been a key ingredient for the planning and design of the muon detector upgrade.

DUNE is an international experiment dedicated to addressing some of the questions at the forefront of particle physics and astrophysics, including the mystifying preponderance of matter over antimatter in the early universe. The dual-site experiment will employ an intense neutrino beam focused on a near and a far detector as it aims to determine the neutrino mass hierarchy and to make high-precision measurements of the PMNS matrix parameters, including the CP-violating phase. It will also stand ready to observe supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector implements liquid argon time-projection chamber (LArTPC) technology, and combines the many tens-of-kiloton fiducial mass necessary for rare event searches with the sub-centimeter spatial resolution required to image those events with high precision. The addition of a photon detection system enhances physics capabilities for all DUNE physics drivers and opens prospects for further physics explorations. Given its size, the far detector will be implemented as a set of modules, with LArTPC designs that differ from one another as newer technologies arise. In the vertical drift LArTPC design, a horizontal cathode bisects the detector, creating two stacked drift volumes in which ionization charges drift towards anodes at either the top or bottom. The anodes are composed of perforated PCB layers with conductive strips, enabling reconstruction in 3D. Light-trap-style photon detection modules are placed both on the cryostat's side walls and on the central cathode where they are optically powered. This Technical Design Report describes in detail the technical implementations of each subsystem of this LArTPC that, together with the other far detector modules and the near detector, will enable DUNE to achieve its physics goals.

The international collaboration designing and constructing the Deep Underground Neutrino Experiment (DUNE) at the Long-Baseline Neutrino Facility (LBNF) has developed a two-phase strategy toward the implementation of this leading-edge, large-scale science project. The 2023 report of the US Particle Physics Project Prioritization Panel (P5) reaffirmed this vision and strongly endorsed DUNE Phase I and Phase II, as did the European Strategy for Particle Physics. While the construction of the DUNE Phase I is well underway, this White Paper focuses on DUNE Phase II planning. DUNE Phase-II consists of a third and fourth far detector (FD) module, an upgraded near detector complex, and an enhanced 2.1 MW beam. The fourth FD module is conceived as a "Module of Opportunity", aimed at expanding the physics opportunities, in addition to supporting the core DUNE science program, with more advanced technologies. This document highlights the increased science opportunities offered by the DUNE Phase II near and far detectors, including long-baseline neutrino oscillation physics, neutrino astrophysics, and physics beyond the standard model. It describes the DUNE Phase II near and far detector technologies and detector design concepts that are currently under consideration. A summary of key R&D goals and prototyping phases needed to realize the Phase II detector technical designs is also provided. DUNE's Phase II detectors, along with the increased beam power, will complete the full scope of DUNE, enabling a multi-decadal program of groundbreaking science with neutrinos.

Liquid argon time projection chambers (TPC) are widely used in neutrino oscillation and dark matter experiments. Detection of scintillation light in liquid argon TPC’s is challenging because of its short wavelength, in the VUV range, and the cryogenic temperatures (∼86 K) at which the sensors must operate. Wavelength shifters (WLS) are typically needed to take advantage of the high Photon Detection Efficiency (PDE) in the visible range of most of photondetectors. The Hamamatsu VUV4 S13370–6075CN SiPMs can directly detect VUV light without the use of WLS, which main benefit is an improved PDE at these short wavelengths, but also the visible light from WLS. The manufacturer (Hamamatsu Photonics K.K.) provides a complete characterization of these devices at room temperature; however, previous studies have indicated a decrease of the PDE at cryogenic temperature for VUV light. In this work, we present the measurement of the PDE of VUV4 SiPMs at cryogenic temperature for different wavelengths in the range [270, 570] nm. A dedicated measurement at 127 nm is also shown.

Doping of liquid argon TPCs (LArTPCs) with a small concentration of xenon is a technique for light-shifting and facilitates the detection of the liquid argon scintillation light. In this paper, we present the results of the first doping test ever performed in a kiloton-scale LArTPC. From February to May 2020, we carried out this special run in the single-phase DUNE Far Detector prototype (ProtoDUNE-SP) at CERN, featuring 720 t of total liquid argon mass with 410 t of fiducial mass. A 5.4 ppm nitrogen contamination was present during the xenon doping campaign. The goal of the run was to measure the light and charge response of the detector to the addition of xenon, up to a concentration of 18.8 ppm. The main purpose was to test the possibility for reduction of non-uniformities in light collection, caused by deployment of photon detectors only within the anode planes. Light collection was analysed as a function of the xenon concentration, by using the pre-existing photon detection system (PDS) of ProtoDUNE-SP and an additional smaller set-up installed specifically for this run. In this paper we first summarize our current understanding of the argon-xenon energy transfer process and the impact of the presence of nitrogen in argon with and without xenon dopant. We then describe the key elements of ProtoDUNE-SP and the injection method deployed. Two dedicated photon detectors were able to collect the light produced by xenon and the total light. The ratio of these components was measured to be about 0.65 as 18.8 ppm of xenon were injected. We performed studies of the collection efficiency as a function of the distance between tracks and light detectors, demonstrating enhanced uniformity of response for the anode-mounted PDS. We also show that xenon doping can substantially recover light losses due to contamination of the liquid argon by nitrogen.