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Using 10.1 × 109 J/ψ events produced by the Beijing Electron Positron Collider (BEPCII) at a center-of-mass energy √s = 3.097 GeV and collected with the BESIII detector, we present a search for the rare semi-leptonic decay J/ψ → D−e+νe + c.c. No excess of signal above background is observed, and an upper limit on the branching fraction ℬ(J/ψ → D−e+νe + c. c.) < 7.1 × 10−8 is obtained at 90% confidence level. This is an improvement of more than two orders of magnitude over the previous best limit.
The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), is effective against T-cell acute lymphoblastic leukaemia (T-ALL) but not against B-cell ALL (B-ALL). The underlying mechanisms have remained elusive. Here, data from pharmacogenomics studies and a panel of ALL cell lines reveal an inverse correlation between nelarabine sensitivity and the expression of SAMHD1, which can hydrolyse and inactivate triphosphorylated nucleoside analogues. Lower SAMHD1 abundance is detected in T-ALL than in B-ALL in cell lines and patient-derived leukaemic blasts. Mechanistically, T-ALL cells display increased SAMHD1 promoter methylation without increased global DNA methylation. SAMHD1 depletion sensitises B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induces AraG resistance. SAMHD1 has a larger impact on nelarabine/AraG than on cytarabine in ALL cells. Opposite effects are observed in acute myeloid leukaemia cells, indicating entity-specific differences. In conclusion, SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine.
The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1 had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineage-specific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.
Though immensely successful, the standard model of particle physics does not offer any explanation as to why our Universe contains so much more matter than antimatter. A key to a dynamically generated matter–antimatter asymmetry is the existence of processes that violate the combined charge conjugation and parity (CP) symmetry1. As such, precision tests of CP symmetry may be used to search for physics beyond the standard model. However, hadrons decay through an interplay of strong and weak processes, quantified in terms of relative phases between the amplitudes. Although previous experiments constructed CP observables that depend on both strong and weak phases, we present an approach where sequential two-body decays of entangled multi-strange baryon–antibaryon pairs provide a separation between these phases. Our method, exploiting spin entanglement between the double-strange Ξ− baryon and its antiparticle2 Ξ¯+
, has enabled a direct determination of the weak-phase difference, (ξP − ξS) = (1.2 ± 3.4 ± 0.8) × 10−2 rad. Furthermore, three independent CP observables can be constructed from our measured parameters. The precision in the estimated parameters for a given data sample size is several orders of magnitude greater than achieved with previous methods3. Finally, we provide an independent measurement of the recently debated Λ decay parameter αΛ (refs. 4,5). The ΛΛ¯
asymmetry is in agreement with and compatible in precision to the most precise previous measurement.
By analyzing 6.32 fb − 1 of e+ e− annihilation data collected at the center-of-mass energies between 4.178 and 4.226 GeV with the BESIII detector, we determine the branching fraction of the leptonic decay D + s → τ + ντ, with τ+ → π + π0¯ντ, to be B D + s → τ + ν τ = (5.29 ± 0.25 stat ± 0.20 syst) %. We estimate the product of the Cabibbo-Kobayashi-Maskawa matrix element |Vcs|and the D + s decay constant f D + s to be f D + s|Vcs| = (244.8 ± 5.8 stat ± 4.8syst) MeV, using the known values of the τ + and D + s masses as well as the D + s lifetime, together with our branching fraction measurement. Combining the value of |Vcs| obtained from a global fit in the standard model and f D + s from lattice quantum chromodynamics, we obtain f D + s = (251.6 ± 5.9 stat ± 4.9syst) MeV and |Vcs| = 0.980 ± 0.023 stat ± 0.019 syst. Using the branching fraction of B D + s → μ + νμ = (5.35±0.21)×10−3, we obtain the ratio of the branching fractions B D + s → τ + ντ/B D +s → μ+νμ = 9.89±0.71, which is consistent with the standard model prediction of lepton flavor universality.
In recent years, the number and type of treatment options in advanced bladder cancer (BC) have been rapidly evolving. To select an effective therapy and spare unnecessary side effects, predictive biomarkers are urgently needed. As the host’s anti-cancer immune response is by far the most effective system to impede malignant tumor growth, immune system-based biomarkers are promising. We have recently described altered proteasomal epitope processing as an effective immune escape mechanism to impair cytotoxic T-cell activity. By altering the neoantigens’ characteristics through different proteasomal peptide cleavage induced by non-synonymous somatic mutations, the ability for T-cell activation was decreased (“processing escapes”). In the present study, we analyzed primary chemo-naïve tissue samples of 26 adjuvant platinum-treated urothelial BC patients using a targeted next-generation sequencing panel followed by the epitope determination of affected genes, a machine-learning based prediction of epitope processing and proteasomal cleavage and of HLA-affinity as well as immune activation. Immune infiltration (immunohistochemistries for CD8, granzyme B, CD45/LCA) was digitally quantified by a pathologist and clinico-pathological and survival data were collected. We detected 145 epitopes with characteristics of a processing escape associated with a higher number of CD8-positive but lower number of granzyme B-positive cells and no association with PD-L1-expression. In addition, a high prevalence of processing escapes was associated with unfavorable overall survival. Our data indicate the presence of processing escapes in advanced BC, potentially creating a tumor-promoting pro-inflammatory environment with lowered anti-cancerous activity and independence from PD-L1-expression. The data also need to be prospectively validated in BC treated with immune therapy.
The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.
Using 7.33 fb−1 of e+e− collision data collected by the BESIII detector at center-of-mass energies between 4.128 and 4.226~GeV, we observe for the first time the decay D±s→ωπ±η with a statistical significance of 7.6σ. The measured branching fraction of this decay is (0.54±0.12±0.04)%, where the first uncertainty is statistical and the second is systematic.
Using a sample of (10.09±0.04)×109 J/ψ events collected with the BESIII detector, a partial wave analysis of J/ψ→γη′η′ is performed.The masses and widths of the observed resonances and their branching fractions are reported. The main contribution is from J/ψ→γf0(2020) with f0(2020)→η′η′, which is found with a significance of greater than 25σ. The product branching fraction B(J/ψ → γf0(2020))⋅B(f0(2020) → η′η′ is measured to be (2.63±0.06(stat.) + 0.31−0.46(syst.))×10−4.
We present the first experimental search for the rare charm decay D0→π0ν¯ν. It is based on an e+e− collision sample consisting of 10.6×10^6 pairs of D0¯D0 mesons collected by the BESIII detector at √s=3.773 GeV, corresponding to an integrated luminosity of 2.93 fb^−1. A data-driven method is used to ensure the reliability of the background modeling. No significant D0→π0ν¯ν signal is observed in data and an upper limit of the branching fraction is set to be 2.1×10^-4 at the 90% confidence level. This is the first experimental constraint on charmed-hadron decays into dineutrino final states.