Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.

Dynamic transcriptional activity and chromatin remodeling of regulatory T cells after varied duration of interleukin-2 receptor signaling.

Regulatory T (Treg) cells require (interleukin-2) IL-2 for their homeostasis by affecting their proliferation, survival and activation. Here we investigated transcriptional and epigenetic changes after acute, periodic and persistent IL-2 receptor (IL-2R) signaling in mouse peripheral Treg cells in vivo using IL-2 or the long-acting IL-2-based biologic mouse IL-2-CD25. We show that initially IL-2R-dependent STAT5 transcription factor-dependent pathways enhanced gene activation, chromatin accessibility and metabolic reprogramming to support Treg cell proliferation. Unexpectedly, at peak proliferation, less accessible chromatin prevailed and was associated with Treg cell contraction. Restimulation of IL-2R signaling after contraction activated signature IL-2-dependent genes and others associated with effector Treg cells, whereas genes associated with signal transduction were downregulated to somewhat temper expansion. Thus, IL-2R-dependent Treg cell homeostasis depends in part on a shift from more accessible chromatin and expansion to less accessible chromatin and contraction. Mouse IL-2-CD25 supported greater expansion and a more extensive transcriptional state than IL-2 in Treg cells, consistent with greater efficacy to control autoimmunity.

Ultrahigh-energy photons up to 1.4 petaelectronvolts from 12 γ-ray Galactic sources.

The extension of the cosmic-ray spectrum beyond 1 petaelectronvolt (PeV; 1015 electronvolts) indicates the existence of the so-called PeVatrons-cosmic-ray factories that accelerate particles to PeV energies. We need to locate and identify such objects to find the origin of Galactic cosmic rays1. The principal signature of both electron and proton PeVatrons is ultrahigh-energy (exceeding 100 TeV) γ radiation. Evidence of the presence of a proton PeVatron has been found in the Galactic Centre, according to the detection of a hard-spectrum radiation extending to 0.04 PeV (ref. 2). Although γ-rays with energies slightly higher than 0.1 PeV have been reported from a few objects in the Galactic plane3-6, unbiased identification and in-depth exploration of PeVatrons requires detection of γ-rays with energies well above 0.1 PeV. Here we report the detection of more than 530 photons at energies above 100 teraelectronvolts and up to 1.4 PeV from 12 ultrahigh-energy γ-ray sources with a statistical significance greater than seven standard deviations. Despite having several potential counterparts in their proximity, including pulsar wind nebulae, supernova remnants and star-forming regions, the PeVatrons responsible for the ultrahigh-energy γ-rays have not yet been firmly localized and identified (except for the Crab Nebula), leaving open the origin of these extreme accelerators.

Diverse polarization angle swings from a repeating fast radio burst source.

Fast radio bursts (FRBs) are millisecond-duration radio transients1,2 of unknown origin. Two possible mechanisms that could generate extremely coherent emission from FRBs invoke neutron star magnetospheres3-5 or relativistic shocks far from the central energy source6-8. Detailed polarization observations may help us to understand the emission mechanism. However, the available FRB polarization data have been perplexing, because they show a host of polarimetric properties, including either a constant polarization angle during each burst for some repeaters9,10 or variable polarization angles in some other apparently one-off events11,12. Here we report observations of 15 bursts from FRB 180301 and find various polarization angle swings in seven of them. The diversity of the polarization angle features of these bursts is consistent with a magnetospheric origin of the radio emission, and disfavours the radiation models invoking relativistic shocks.

Phase II clinical trial of neoadjuvant anti-PD-1 (toripalimab) combined with axitinib in resectable mucosal melanoma.

BACKGROUND: The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months in a phase Ib trial. It was hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma, so we conducted this trial. PATIENTS AND METHODS: This single-arm phase II trial enrolled patients with resectable mucosal melanoma. Patients received toripalimab 3 mg/kg once every 2 weeks (Q2W) plus axitinib 5 mg two times a day (b.i.d.) for 8 weeks as neoadjuvant therapy, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2 ± 1weeks after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to the International Neoadjuvant Melanoma Consortium recommendations. RESULTS: Between August 2019 and October 2021, 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median follow-up time was 34.2 months (95% confidence interval 20.4-48.0 months). The pathologic response rate was 33.3% (8/24; 4 pathological complete responses and 4 pathological partial responses). The median event-free survival for all patients was 11.1 months (95% confidence interval 5.3-16.9 months). The median overall survival was not reached. Neoadjuvant therapy was tolerable with 8 (27.5%) grade 3-4 treatment-related adverse events and no treatment-related deaths. Tissue samples of 17 patients at baseline and after surgery were collected (5 responders and 12 nonresponders). Multiplex immunohistochemistry demonstrated a significant increase in CD3+ (P = 0.0032) and CD3+CD8+ (P = 0.0038) tumor-infiltrating lymphocytes after neoadjuvant therapy, particularly in pathological responders. CONCLUSIONS: Neoadjuvant toripalimab combined with axitinib in resectable mucosal melanoma demonstrated a promising pathologic response rate with significantly increased infiltrating CD3+ and CD3+CD8+ T cells after therapy.

Ensemble methods of rank-based trees for single sample classification with gene expression profiles.

Building Single Sample Predictors (SSPs) from gene expression profiles presents challenges, notably due to the lack of calibration across diverse gene expression measurement technologies. However, recent research indicates the viability of classifying phenotypes based on the order of expression of multiple genes. Existing SSP methods often rely on Top Scoring Pairs (TSP), which are platform-independent and easy to interpret through the concept of "relative expression reversals". Nevertheless, TSP methods face limitations in classifying complex patterns involving comparisons of more than two gene expressions. To overcome these constraints, we introduce a novel approach that extends TSP rules by constructing rank-based trees capable of encompassing extensive gene-gene comparisons. This method is bolstered by incorporating two ensemble strategies, boosting and random forest, to mitigate the risk of overfitting. Our implementation of ensemble rank-based trees employs boosting with LogitBoost cost and random forests, addressing both binary and multi-class classification problems. In a comparative analysis across 12 cancer gene expression datasets, our proposed methods demonstrate superior performance over both the k-TSP classifier and nearest template prediction methods. We have further refined our approach to facilitate variable selection and the generation of clear, precise decision rules from rank-based trees, enhancing interpretability. The cumulative evidence from our research underscores the significant potential of ensemble rank-based trees in advancing disease classification via gene expression data, offering a robust, interpretable, and scalable solution. Our software is available at https://CRAN.R-project.org/package=ranktreeEnsemble .

Inhomogeneous Photosusceptibility of VO_{2} Films at the Nanoscale.

Pump-probe nano-optical experiments were used to study the light-induced insulator to metal transition (IMT) in thin films of vanadium dioxide (VO_{2}), a prototypical correlated electron system. We show that inhomogeneous optical contrast is prompted by spatially uniform photoexcitation, indicating an inhomogeneous photosusceptibility of VO_{2}. We locally characterize temperature and time dependent variations of the photoexcitation threshold necessary to induce the IMT on picosecond timescales with hundred nanometer spatial resolution. We separately measure the critical temperature T_{L}, where the IMT onsets and the local transient electronic nano-optical contrast at the nanoscale. Our data reveal variations in the photosusceptibility of VO_{2} within nanoscopic regions characterized by the same critical temperature T_{L} where metallic domains can first nucleate.

First Study of Antihyperon-Nucleon Scattering Λ[over ¯]p→Λ[over ¯]p and Measurement of Λp→Λp Cross Section.

Using (10.087±0.044)×10^{9} J/ψ events collected with the BESIII detector at the BEPCII storage ring, the processes Λp→Λp and Λ[over ¯]p→Λ[over ¯]p are studied, where the Λ/Λ[over ¯] baryons are produced in the process J/ψ→ΛΛ[over ¯] and the protons are the hydrogen nuclei in the cooling oil of the beam pipe. Clear signals are observed for the two reactions. The cross sections in -0.9≤cosθ_{Λ/Λ[over ¯]}≤0.9 are measured to be σ(Λp→Λp)=(12.2±1.6_{stat}±1.1_{syst}) and σ(Λ[over ¯]p→Λ[over ¯]p)=(17.5±2.1_{stat}±1.6_{syst}) mb at the Λ/Λ[over ¯] momentum of 1.074 GeV/c within a range of ±0.017 GeV/c, where the θ_{Λ/Λ[over ¯]} are the scattering angles of the Λ/Λ[over ¯] in the Λp/Λ[over ¯]p rest frames. Furthermore, the differential cross sections of the two reactions are also measured, where there is a slight tendency of forward scattering for Λp→Λp, and a strong forward peak for Λ[over ¯]p→Λ[over ¯]p. We present an approach to extract the total elastic cross sections by extrapolation. The study of Λ[over ¯]p→Λ[over ¯]p represents the first study of antihyperon-nucleon scattering, and these new measurements will serve as important inputs for the theoretical understanding of the (anti)hyperon-nucleon interaction.

Determination of Spin-Parity Quantum Numbers of X(2370) as 0

Based on (10087±44)×10^{6} J/ψ events collected with the BESIII detector, a partial wave analysis of the decay J/ψ→γK_{S}^{0}K_{S}^{0}η^{'} is performed. The mass and width of the X(2370) are measured to be 2395±11(stat)_{-94}^{+26}(syst) MeV/c^{2} and 188_{-17}^{+18}(stat)_{-33}^{+124}(syst) MeV, respectively. The corresponding product branching fraction is B[J/ψ→γX(2370)]×B[X(2370)→f_{0}(980)η^{'}]×B[f_{0}(980)→K_{S}^{0}K_{S}^{0}]=(1.31±0.22(stat)_{-0.84}^{+2.85}(syst))×10^{-5}. The statistical significance of the X(2370) is greater than 11.7σ and the spin parity is determined to be 0^{-+} for the first time. The measured mass and spin parity of the X(2370) are consistent with the predictions of the lightest pseudoscalar glueball.

Observation of Structures in the Processes e

We present measurements of the Born cross sections for the processes e^{+}e^{-}→ωχ_{c1} and ωχ_{c2} at center-of-mass energies sqrt[s] from 4.308 to 4.951 GeV. The measurements are performed with data samples corresponding to an integrated luminosity of 11.0 fb^{-1} collected with the BESIII detector operating at the Beijing Electron Positron Collider storage ring. Assuming the e^{+}e^{-}→ωχ_{c2} signals come from a single resonance, the mass and width are determined to be M=(4413.6±9.0±0.8) MeV/c^{2} and Γ=(110.5±15.0±2.9) MeV, respectively, which is consistent with the parameters of the well-established resonance ψ(4415). In addition, we also use one single resonance to describe the e^{+}e^{-}→ωχ_{c1} line shape and determine the mass and width to be M=(4544.2±18.7±1.7) MeV/c^{2} and Γ=(116.1±33.5±1.7) MeV, respectively. The structure of this line shape, observed for the first time, requires further understanding.

First Observation of a Three-Resonance Structure in e

We report the measurement of the inclusive cross sections for e^{+}e^{-}→nOCH (where nOCH denotes non-open charm hadrons) with improved precision at center-of-mass (c.m.) energies from 3.645 to 3.871 GeV. We observe three resonances: R(3760), R(3780), and R(3810) with significances of 8.1σ, 13.7σ, and 8.8σ, respectively. The R(3810) state is observed for the first time, while the R(3760) and R(3780) states are observed for the first time in the nOCH cross sections. Two sets of resonance parameters describe the energy-dependent line shape of the cross sections well. In set I [set II], the R(3810) state has mass (3805.7±1.1±2.7) [(3805.7±1.1±2.7)] MeV/c^{2}, total width (11.6±2.9±1.9) [(11.5±2.8±1.9)] MeV, and an electronic width multiplied by the nOCH decay branching fraction of (10.9±3.8±2.5) [(11.0±3.4±2.5)] eV. In addition, we measure the branching fractions B[R(3760)→nOCH]=(25.2±16.1±30.4)%[(6.4±4.8±7.7)%] and B[R(3780)→nOCH]=(12.3±6.6±8.3)%[(10.4±4.8±7.0)%] for the first time. The R(3760) state can be interpreted as an open-charm (OC) molecular state, but containing a simple four-quark state component. The R(3810) state can be interpreted as a hadrocharmonium state.

Coupled-Channel Analysis of the χ_{c1}(3872) Line Shape with BESIII Data.

We perform a study of the χ_{c1}(3872) line shape using the data samples of e^{+}e^{-}→γχ_{c1}(3872), χ_{c1}(3872)→D^{0}D[over ¯]^{0}π^{0}, and π^{+}π^{-}J/ψ collected with the BESIII detector. The effects of the coupled channels and the off-shell D^{*0} are included in the parametrization of the line shape. The line shape mass parameter is obtained to be M_{X}=(3871.63±0.13_{-0.05}^{+0.06}) MeV. Two poles are found on the first and second Riemann sheets corresponding to the D^{*0}D[over ¯]^{0} branch cut. The pole location on the first sheet is much closer to the D^{*0}D[over ¯]^{0} threshold than the other, and is determined to be 7.04±0.15_{-0.08}^{+0.07} MeV above the D^{0}D[over ¯]^{0}π^{0} threshold with an imaginary part -0.19±0.08_{-0.19}^{+0.14} MeV.

Observation of the Anomalous Shape of X(1840) in J/ψ→γ3(π

Using a sample of (10087±44)×10^{6} J/ψ events, which is about 45 times larger than that was previously analyzed, a further investigation on the J/ψ→γ3(π^{+}π^{-}) decay is performed. A significant distortion at 1.84 GeV/c^{2} in the line shape of the 3(π^{+}π^{-}) invariant mass spectrum is observed for the first time, which could be resolved by two overlapping resonant structures, X(1840) and X(1880). The new state X(1880) is observed with a statistical significance larger than 10σ. The mass and width of X(1880) are determined to be 1882.1±1.7±0.7 MeV/c^{2} and 30.7±5.5±2.4 MeV, respectively, which indicates the existence of a pp[over ¯] bound state.

Measurements of Normalized Differential Cross Sections of Inclusive η Production in e

Using data samples collected with the BESIII detector operating at the BEPCII storage ring, the cross section of the inclusive process e^{+}e^{-}→η+X, normalized by the total cross section of e^{+}e^{-}→hadrons, is measured at eight center-of-mass energy points from 2.0000 to 3.6710 GeV. These are the first measurements with momentum dependence in this energy region. Our measurement shows a significant discrepancy compared to the existing fragmentation functions. To address this discrepancy, a new QCD analysis is performed at the next-to-next-to-leading order with hadron mass corrections and higher twist effects, which can explain both the established high-energy data and our measurements reasonably well.

First Measurement of the Decay Asymmetry in the Pure W-Boson-Exchange Decay Λ_{c}

Based on 4.4 fb^{-1} of e^{+}e^{-} annihilation data collected at the center-of-mass energies between 4.60 and 4.70 GeV with the BESIII detector at the BEPCII collider, the pure W-boson-exchange decay Λ_{c}^{+}→Ξ^{0}K^{+} is studied with a full angular analysis. The corresponding decay asymmetry is measured for the first time to be α_{Ξ^{0}K^{+}}=0.01±0.16(stat)±0.03(syst). This result reflects the noninterference effect between the S- and P-wave amplitudes. The phase shift between S- and P-wave amplitudes has two solutions, which are δ_{p}-δ_{s}=-1.55±0.25(stat)±0.05(syst) rad or 1.59±0.25(stat)±0.05(syst) rad.

Observation of D_{s}

By analyzing 7.33 fb^{-1} of e^{+}e^{-} annihilation data collected at center-of-mass energies between 4.128 and 4.226 GeV with the BESIII detector, we report the observation of the semileptonic decay D_{s}^{+}→η^{'}µ^{+}ν_{µ}, with a statistical significance larger than 10σ, and the measurements of the D_{s}^{+}→ηµ^{+}ν_{µ} and D_{s}^{+}→η^{'}µ^{+}ν_{µ} decay dynamics for the first time. The branching fractions of D_{s}^{+}→ηµ^{+}ν_{µ} and D_{s}^{+}→η^{'}µ^{+}ν_{µ} are determined to be (2.235±0.051_{stat}±0.052_{syst})% and (0.801±0.055_{stat}±0.028_{syst})%, respectively, with precision improved by factors of 6.0 and 6.6 compared to the previous best measurements. Combined with the results for the decays D_{s}^{+}→ηe^{+}ν_{e} and D_{s}^{+}→η^{'}e^{+}ν_{e}, the ratios of the decay widths are examined both inclusively and in several ℓ^{+}ν_{ℓ} four-momentum transfer ranges. No evidence for lepton flavor universality violation is found within the current statistics. The products of the hadronic form factors f_{+,0}^{η^{(')}}(0) and the c→s Cabibbo-Kobayashi-Maskawa matrix element |V_{cs}| are determined. The results based on the two-parameter series expansion are f_{+,0}^{η}(0)|V_{cs}|=0.452±0.010_{stat}±0.007_{syst} and f_{+,0}^{η^{'}}(0)|V_{cs}|=0.504±0.037_{stat}±0.012_{syst}, which help to constrain present models on f_{+,0}^{η^{(')}}(0). The forward-backward asymmetries are determined to be ⟨A_{FB}^{η}⟩=-0.059±0.031_{stat}±0.005_{syst} and ⟨A_{FB}^{η^{'}}⟩=-0.064±0.079_{stat}±0.006_{syst} for the first time, which are consistent with the theoretical calculation.

Investigation of the ΔI=1/2 Rule and Test of CP Symmetry through the Measurement of Decay Asymmetry Parameters in Ξ

Using (10087±44)×10^{6} J/ψ events collected with the BESIII detector, numerous Ξ^{-} and Λ decay asymmetry parameters are simultaneously determined from the process J/ψ→Ξ^{-}Ξ[over ¯]^{+}→Λ(pπ^{-})π^{-}Λ[over ¯](n[over ¯]π^{0})π^{+} and its charge-conjugate channel. The precisions of α_{Λ0} for Λ→nπ^{0} and α[over ¯]_{Λ0} for Λ[over ¯]→n[over ¯]π^{0} compared to world averages are improved by factors of 4 and 1.7, respectively. The ratio of decay asymmetry parameters of Λ→nπ^{0} to that of Λ→pπ^{-}, ⟨α_{Λ0}⟩/⟨α_{Λ-}⟩, is determined to be 0.873±0.012_{-0.010}^{+0.011}, where the first and the second uncertainties are statistical and systematic, respectively. The ratio is smaller than unity more than 5σ, which signifies the existence of the ΔI=3/2 transition in Λ for the first time. Besides, we test for CP symmetry in Ξ^{-}→Λπ^{-} and in Λ→nπ^{0} with the best precision to date.

Observation of Significant Flavor-SU(3) Breaking in the Kaon Wave Function at 12

We present cross sections for the reaction e^{+}e^{-}→K_{S}^{0}K_{L}^{0} at center-of-mass energies ranging from 3.51 to 4.95 GeV using data samples collected in the BESIII experiment, corresponding to a total integrated luminosity of 26.5 fb^{-1}. The ratio of neutral-to-charged kaon form factors at large momentum transfers (12

Observation of D

We perform for the first time an amplitude analysis of the decay D^{+}→K_{S}^{0}π^{+}η and report the observation of the decay D^{+}→K_{S}^{0}a_{0}(980)^{+} using 2.93 fb^{-1} of e^{+}e^{-} collision data taken at a center-of-mass energy of 3.773 GeV with the BESIII detector. As the only W-annihilation-free decay among D to a_{0}(980) pseudoscalar, D^{+}→K_{S}^{0}a_{0}(980)^{+} is the ideal decay in extracting the contributions of the W-emission amplitudes involving a_{0}(980) and to study the final-state interactions. The absolute branching fraction of D^{+}→K_{S}^{0}π^{+}η is measured to be (1.27±0.04_{stat}±0.03_{syst})%. The branching fractions of intermediate processes D^{+}→K_{S}^{0}a_{0}(980)^{+} with a_{0}(980)^{+}→π^{+}η and D^{+}→π^{+}K[over ¯]_{0}^{*}(1430)^{0} with K[over ¯]_{0}^{*}(1430)^{0}→K_{S}^{0}η are measured to be (1.33±0.05_{stat}±0.04_{syst})% and (0.14±0.03_{stat}±0.01_{syst})%, respectively.