Abstract Loss of the Y chromosome (LOY) is associated with poor survival across multiple solid tumors, yet the underlying molecular mechanisms remain poorly understood. Here, we identify LOY as a central driver of lineage plasticity and epigenetic heterogeneity in lung adenocarcinoma. Integrating multi-omic profiling of primary samples with isogenic cellular models, we show that LOY triggers epithelial-to-mesenchymal transition (EMT). Mechanistically, LOY causes haploinsufficiency of dosage-sensitive regulators, leading to widespread DNA hypomethylation at EMT gene promoters, including THY1 and LOX . Single-cell multi-omic analyses demonstrate that LOY induces epigenetic heterogeneity, destabilizes the chromatin landscape, and increases lineage plasticity, enabling rapid cellular adaptation to metabolic and genotoxic stress. Moreover, LOY-induced plasticity facilitates tumor engraftment and metastatic dissemination in vivo . These findings establish Y-linked gene dosage as a critical guardian of epigenetic stability, providing a mechanistic rationale for how its loss amplifies phenotypic diversity and lineage plasticity, ultimately driving adverse clinical outcomes in LOY patients.

Abstract Loss of the Y chromosome (LOY) is among the most frequent somatic alterations in the blood of aging men. In cancer, LOY is associated with poor survival across multiple solid entities, including non-small cell lung cancer. Yet, the molecular mechanisms linking LOY and adverse outcomes remain poorly understood. Beyond sex-determining loci, the Y chromosome encodes dosage-sensitive genes, including two epigenetic regulators, whose X-linked homologs escape X-inactivation in females. We hypothesized that LOY results in haploinsufficiency of these regulatory genes, promoting tumor cell plasticity and heterogeneity. We investigated the consequences of LOY in lung adenocarcinoma (LUAD), the most prevalent lung cancer subtype, showing higher incidence and mortality in men. We performed whole-genome and single-cell RNA sequencing of paired tumor and matched normal lung tissue from male LUAD patients, complemented by public datasets. LOY was enriched in malignant cells and less frequent in the tumor microenvironment. To define tumor-cell-intrinsic effects, we generated isogenic A549 single-cell clones with or without the Y chromosome. LOY clones and primary LOY LUAD samples exhibited strong activation of epithelial-to-mesenchymal transition (EMT) programs. Genes that were consistently upregulated in LOY compared to ROY included THY1, LOX, and CDH2, which we also found to be highly abundant on the protein level. These effects were accompanied by increased cell-state plasticity, enhanced adaptation to metabolic and genotoxic stress. At the epigenetic level, we found widespread differences in DNA methylation patterns, especially at gene promoters of EMT genes, indicating an epigenetic underpinning of the phenotype. At the single-cell level, LOY clones showed increased epigenetic and transcriptional heterogeneity. Functionally, LOY conferred a selective advantage in vivo, promoting tumor engraftment and metastatic outgrowth. Together, these findings identify LOY as a previously unrecognized driver of EMT activation and tumor plasticity through epigenetic and transcriptional reprogramming, providing a mechanistic explanation for its association with poor therapy response and adverse clinical outcome in male lung adenocarcinoma. Citation Format: Kathleen Schlüter, Mei-Ju May Chen, Gizem Altun, Sergio Manzano Sanchez, Dung-Chi Wu, Nan Zhang, Ofir Griess, Luc Husemann, Fabian Bradic, Joseph Cornick, Oliver Mücke, Riccardo Moro, Katherine Kelly, Sara Chocarro, Etienne Sollier, Maria Jose Alonso-De Gennaro, Siavash Mansouri, Madeleine Dorsch, Patricia Munteanu, Balazs Hegedüs, Hauke Winter, Laura V. Klotz, Mark Kriegsmann, Felix JF Herth, Marc A. Schneider, Daniel Kazdal, Albrecht Stenzinger, Alexander Schramm, Felix J. Hartmann, Pavlo Lutsik, Ursula Klingmüller, Rajkumar Savai, Rocio Sotillo, Barbara M. Grüner, Guy Ron, Efrat Shema, Michael Scherer, Christoph Plass, Maria Llamazares-Prada. Y chromosome loss drives cellular plasticity through single-cell epigenetic and transcriptional heterogeneity in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB309.

Diffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations on the wiring of the epigenetic network, we applied a single-cell approach to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is epistatic over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present tools to reconstruct known interactions within the epigenetic network, as well as reveal potential novel cross talk between various modifications, supported by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells.

The MUon Scattering Experiment (MUSE) was motivated by the proton radius puzzle arising from the discrepancy between muonic hydrogen spectroscopy and electron-proton measurements. The MUSE physics goals also include testing lepton universality, precisely measuring two-photon exchange contribution, and testing radiative corrections. MUSE addresses these physics goals through simultaneous measurement of high precision cross sections for electron-proton and muon-proton scattering using a mixed-species beam. The experiment will run at both positive and negative beam polarities. Measuring precise cross sections requires understanding both the incident beam energy and the radiative corrections. For this purpose, a lead-glass calorimeter was installed at the end of the beam line in the MUSE detector system. In this article we discuss the detector specifications, calibration and performance. We demonstrate that the detector performance is well reproduced by simulation, and meets experimental requirements.

Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2mut) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDHmut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single-cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2-HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.

The role of the electron-helicity-dependent cross-section term and the structure function f01′ in the quasi-elastic A(e→,e′p) process was studied. The f01′ was measured for proton knockout from the 1d3/2 shell in 40Ca via the 40Ca(e→,e′p)39Kg.s. reaction, leaving the residual nucleus in a well-defined state. It requires a longitudinally polarized electron beam and out-of-plane proton detection. This structure function vanishes in the absence of final-state interactions (FSI) involving the ejected proton. Presented are the dependencies of f01′ on the missing momentum (closely related to the initial proton’s Fermi momentum) and the angle between the knocked-out proton and the virtual photon momenta. The role of the spin-orbit interaction in FSI through the L→·S→ term in a nuclear optical potential is discussed.

Doppler Broadening (DB) of annihilation radiation is a well-established technique within Positron Annihilation Spectroscopy (PAS), used for probing the electronic structure of materials. The analysis of DB experimental data relies on gamma spectroscopy analysis tools, while depth profiling using variable-energy slow positron beams depends on solving the positron diffusion equation. Traditional Variable Energy Doppler Broadening (VEDB) analysis tools, such as VEPFIT and ROYPROF, often present limitations due to outdated interfaces and lack of integration with comprehensive spectroscopy analysis platforms. Addressing these challenges, an open-source Python package for PAS analysis, PyPAS, is introduced. PyPAS offers functionalities including Coincidence Doppler Broadening (CDB) filtering, two-dimensional CDB analysis with DB and resolution extraction, and computation of lineshape parameters (S and W). Furthermore, it integrates modules for generating thermal positron implantation profiles based on established models, solving positron diffusion equations using finite-difference methods and optimizing diffusion length. This work presents the architecture of the PyPAS package and the validation results and demonstrates the application of the package through case studies.

The analysis of cell-free tumor DNA (ctDNA) and proteins in the blood of patients with cancer potentiates a new generation of non-invasive diagnostic approaches. However, confident detection of tumor-originating markers is challenging, especially in the context of brain tumors, where these analytes in plasma are extremely scarce. Here, we apply a sensitive single-molecule technology to profile multiple histone modifications on individual nucleosomes from the plasma of patients with diffuse midline glioma (DMG). The system reveals epigenetic patterns unique to DMG, significantly differentiating this group of patients from healthy subjects or individuals diagnosed with other cancer types. We further develop a method to directly quantify the tumor-originating oncoproteins, lysine 27 to methionine substitution in histone H3 (H3-K27M) and mutant p53, from <1 mL of plasma, allowing for the accurate molecular classification of patients with DMG. We show that our strategy correlates with MRI and droplet-digital PCR (ddPCR) measurements of ctDNA, highlighting the clinical potential of single-molecule-based, multi-parametric assays for DMG diagnosis and treatment monitoring.

The ratio of the transverse and longitudinal components of polarization transfer to protons in the quasielastic ((e) over right arrow, e'(p) over right arrow) reaction, P'(x)/P'(z), is sensitive to the proton's electromagnetic form factor ratio, G(E)/G(M). To explore density-dependent in-medium modifications, a comparison of polarization transfer ratios involving protons from distinct nuclear shells, each with different local nuclear densities, has been proposed. In this study, we present such comparisons between four shells, 1s(1/2), 1p(3/2) in C-12 and 1d(3/2), 2s(1/2) in Ca-40. In an effort to account for other many-body effects that may differ between shells, we use a state-of-the-art relativistic distorted-wave impulse-approximation (RDWIA) calculation and present the double ratios (P'(x)/P'(z))(Data)/(P'(x)/P'(z))(RDWIA) as well as the superratios [(P'(x)/P'(z))(A)/(P'(x)/P'(z))(B)](Data)/[(P'(x)/P'(z))(A)/(P'(x)/P'(z))(B)](RDWIA), for chosen shells A and B, as a function of effective local nuclear densities. We find that double ratios for individual shells show a dependence on the probed effective nuclear densities. Studying the super-ratios, we observed a systematic variation between pairs of higher- and lower-density shells.

The ratio of the transverse and longitudinal component of polarization transfer to protons in quasi-elastic $(\vec{e}, e^{\prime} \vec{p}\,)$ reaction, $P^{\prime}_x/P^{\prime}_z$, is sensitive to the proton's electromagnetic form factor ratio, $G_E/G_M$. To explore density-dependent in-medium modifications, a comparison of polarization transfer ratios involving protons from distinct nuclear shells, each with different local nuclear densities, has been proposed. In this study, we present such comparisons between four shells, $1s_{1/2}$, $1p_{3/2}$ in $^{12}\mathrm{C}$ and $1d_{3/2}$, $2s_{1/2}$ in $^{40}\mathrm{Ca}$. In an effort to account for other many-body effects that may differ between shells, we use state-of-the-art relativistic distorted-wave impulse-approximation (RDWIA) calculation and present the double ratios, $(P^{\prime}_x/P^{\prime}_z)_{\rm Data}/(P^{\prime}_x/P^{\prime}_z)_{\rm RDWIA}$ as well as the super ratios, $\left[(P^{\prime}_x/P^{\prime}_z)_{\rm A}/(P^{\prime}_x/P^{\prime}_z)_{\rm B}\right]_{\rm Data}/\left[(P^{\prime}_x/P^{\prime}_z)_{\rm A}/(P^{\prime}_x/P^{\prime}_z)_{\rm B}\right]_{\rm RDWIA}$, for chosen shells A and B, as a function of effective local nuclear densities. We find that double ratios for individual shells show a dependence on the probed effective nuclear densities. Studying the ratios, we observed a systematic variation between pairs of higher- and lower-density shells.

The MUSE experiment at the Paul Scherrer Institute is measuring elastic lepton-proton scattering cross sections in a four-momentum transfer range from $Q^2$ of approximately 0.002 to 0.08 GeV$^2$ using positively and negatively charged electrons and muons. The extraction of the Born cross sections from the experimental data requires radiative corrections. Estimates of the instrumental uncertainties in those corrections have been made using the ESEPP event generator. The results depend in particular on the minimum lepton momentum that contributes to the experimental cross section and the fraction of events with hard initial-state radiation that is detected in the MUSE calorimeter and is excluded from the data. These results show that the angular-dependent instrumental uncertainties in radiative corrections to the electron cross section are better than 0.4 % and are negligible for the muon cross section.

Diffuse midline gliomas (DMGs) are aggressive and fatal pediatric tumors of the central nervous system that are highly resistant to treatments. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor growth reduction in mice treated with the drug combination. These results highlight the combined treatment with PIN1 and HDAC inhibitors as a promising therapeutic approach for these aggressive tumors.

The construction and successive first operation of a slow positron beam at The Hebrew University of Israel are reported here. The beam follows a traditional design, using a 22Na source, and a Tungsten moderator. It is designed to allow a combined measurement of Doppler-Broadening (DB), sample conductivity, and sample in-situ cooling, with the flexibility to add more detection options in the future. The beam energy varies between 0.03 keV and 30 keV. The detection system consists of two high-purity Germanium detectors, facing each other, allowing coincidence DB measurements. Event readout is done using a state-of-the-art compact desktop system. The beam has been successfully tested by using it to characterize annealed Copper (Cu) samples. Three samples were measured at various energies (0.5 keV–16.5 keV), one before any treatment and two annealed at 250 °C and 500 °C. The results, fitted using VEPFIT, show consistent behavior with previous measurements.

The ECCE detector has been recommended as the selected reference detector for the future Electron-Ion Collider (EIC). A series of simulation studies have been carried out to validate the physics feasibility of the ECCE detector. In this paper, detailed studies of heavy flavor hadron and jet reconstruction and physics projections with the ECCE detector performance and different magnet options will be presented. The ECCE detector has enabled precise EIC heavy flavor hadron and jet measurements with a broad kinematic coverage. These proposed heavy flavor measurements will help systematically study the hadronization process in vacuum and nuclear medium especially in the underexplored kinematic region.

This white paper provides a comprehensive review of our present understanding of experimental neutrino anomalies that remain unresolved, charting the progress achieved over the last decade at the experimental and phenomenological level, and sets the stage for future programmatic prospects in addressing those anomalies. It is purposed to serve as a guiding and motivational "encyclopedic" reference, with emphasis on needs and options for future exploration that may lead to the ultimate resolution of the anomalies. We see the main experimental, analysis, and theory-driven thrusts that will be essential to achieving this goal being: 1) Cover all anomaly sectors -- given the unresolved nature of all four canonical anomalies, it is imperative to support all pillars of a diverse experimental portfolio, source, reactor, decay-at-rest, decay-in-flight, and other methods/sources, to provide complementary probes of and increased precision for new physics explanations; 2) Pursue diverse signatures -- it is imperative that experiments make design and analysis choices that maximize sensitivity to as broad an array of these potential new physics signatures as possible; 3) Deepen theoretical engagement -- priority in the theory community should be placed on development of standard and beyond standard models relevant to all four short-baseline anomalies and the development of tools for efficient tests of these models with existing and future experimental datasets; 4) Openly share data -- Fluid communication between the experimental and theory communities will be required, which implies that both experimental data releases and theoretical calculations should be publicly available; and 5) Apply robust analysis techniques -- Appropriate statistical treatment is crucial to assess the compatibility of data sets within the context of any given model.

The evaluation of the measurement of double-spin asymmetries for charge-separated pions and kaons produced in deep-inelastic scattering from the proton using the ECCE detector design concept is presented, for the combinations of lepton and hadron beam energies of 5 x 41 GeV2 and 18 x 275 GeV2. The study uses unpolarised simulated data that are processed through a full GEANT simulation of the detector. These data are then reweighted at the parton level with DSSV helicity distributions and DSS fragmentation functions, in order to generate the relevant asymmetries, and subsequently analysed. The performed analysis shows that the ECCE detector concept provides the resolution and acceptance, with a broad coverage in kinematic phase space, needed for a robust extraction of asymmetries. This, in turn, allows for a precise extraction of sea-quark helicity distributions.

The analysis of cell-free DNA (cfDNA) in plasma provides information on pathological processes in the body. Blood cfDNA is in the form of nucleosomes, which maintain their tissue- and cancer-specific epigenetic state. We developed a single-molecule multiparametric assay to comprehensively profile the epigenetics of plasma-isolated nucleosomes (EPINUC), DNA methylation and cancer-specific protein biomarkers. Our system allows for high-resolution detection of six active and repressive histone modifications and their ratios and combinatorial patterns on millions of individual nucleosomes by single-molecule imaging. In addition, our system provides sensitive and quantitative data on plasma proteins, including detection of non-secreted tumor-specific proteins, such as mutant p53. EPINUC analysis of a cohort of 63 colorectal cancer, 10 pancreatic cancer and 33 healthy plasma samples detected cancer with high accuracy and sensitivity, even at early stages. Finally, combining EPINUC with direct single-molecule DNA sequencing revealed the tissue of origin of colorectal, pancreatic, lung and breast tumors. EPINUC provides multilayered information of potential clinical relevance from limited (<1 ml) liquid biopsy material.

Exclusive heavy quarkonium photoproduction is one of the most popular processes in EIC, which has a large cross section and a simple final state. Due to the gluonic nature of the exchange Pomeron, this process can be related to the gluon distributions in the nucleus. The momentum transfer dependence of this process is sensitive to the interaction sites, which provides a powerful tool to probe the spatial distribution of gluons in the nucleus. Recently the problem of the origin of hadron mass has received lots of attention in determining the anomaly contribution $M_{a}$. The trace anomaly is sensitive to the gluon condensate, and exclusive production of quarkonia such as J/$ψ$ and $Υ$ can serve as a sensitive probe to constrain it. In this paper, we present the performance of the ECCE detector for exclusive J/$ψ$ detection and the capability of this process to investigate the above physics opportunities with ECCE.

The recently approved Electron-Ion Collider (EIC) will provide a unique new opportunity for searches of charged lepton flavor violation (CLFV) and other new physics scenarios. In contrast to the $e \leftrightarrow \mu$ CLFV transition for which very stringent limits exist, there is still a relatively large discovery space for the $e \to \tau$ CLFV transition, potentially to be explored by the EIC. With the latest detector design of ECCE (EIC Comprehensive Chromodynamics Experiment) and projected integral luminosity of the EIC, we find the $\tau$-leptons created in the DIS process $ep\to \tau X$ are expected to be identified with high efficiency. A first ECCE simulation study, restricted to the 3-prong $\tau$-decay mode and with limited statistics for the Standard Model backgrounds, estimates that the EIC will be able to improve the current exclusion limit on $e\to \tau$ CLFV by an order of magnitude.

The Electron-Ion Collider (EIC) is a cutting-edge accelerator facility that will study the nature of the "glue" that binds the building blocks of the visible matter in the universe. The proposed experiment will be realized at Brookhaven National Laboratory in approximately 10 years from now, with detector design and R D currently ongoing. Notably, EIC is one of the first large-scale facilities to leverage Artificial Intelligence (AI) already starting from the design and R D phases. The EIC Comprehensive Chromodynamics Experiment (ECCE) is a consortium that proposed a detector design based on a 1.5T solenoid. The EIC detector proposal review concluded that the ECCE design will serve as the reference design for an EIC detector. Herein we describe a comprehensive optimization of the ECCE tracker using AI. The work required a complex parametrization of the simulated detector system. Our approach dealt with an optimization problem in a multidimensional design space driven by multiple objectives that encode the detector performance, while satisfying several mechanical constraints. We describe our strategy and show results obtained for the ECCE tracking system. The AI-assisted design is agnostic to the simulation framework and can be extended to other sub-detectors or to a system of sub-detectors to further optimize the performance of the EIC detector.