A snapshot of cancer-associated thromboembolic disease in 2018-2019: First data from the TESEO prospective registry

BACKGROUND: The ever-growing complexity of cancer-associated thrombosis (CAT), with new antineoplastic drugs and anticoagulants, distinctive characteristics, and decisions with low levels of evidence, justifies this registry. METHOD: TESEO is a prospective registry promoted by the Spanish Society of Medical Oncology to which 34 centers contribute cases. It seeks to provide an epidemiological description of CAT in Spain. RESULTS: Participants (N=939) with CAT diagnosed between July 2018 and December 2019 were recruited. Most subjects had advanced colon (21.4%), non-small cell lung (19.2%), and breast (11.1%) cancers, treated with dual-agent chemotherapy (28.4%), monochemotherapy (14.4%), or immune checkpoint inhibitors (3.6%). Half (51%) were unsuspected events, albeit only 57.1% were truly asymptomatic. Pulmonary embolism (PE) was recorded in 571 (58.3%); in 120/571 (21.0%), there was a concurrent deep venous thromboembolism (VTE). Most initially received low molecular weight heparin (89.7%). Suspected and unsuspected VTE had an OS rate of 9.9 (95% CI, 7.3-non-computable) and 14.4 months (95% CI, 12.6-non-computable) (p=0.00038). Six-month survival was 80.9%, 55.9%, and 55.5% for unsuspected PE, unsuspected PE admitted for another reason, and suspected PE, respectively (p<0.0001). The 12-month cumulative incidence of venous rethrombosis was 7.1% (95% CI, 4.7-10.2) in stage IV vs 3.0% (95% CI, 0.9-7.1) in stages I-III. The 12-month cumulative incidence of major/clinically relevant bleeding was 9.6% (95% CI, 6.1-14.0) in the presence of risk factors. CONCLUSION: CAT continues to be a relevant problem in the era of immunotherapy and targeted therapies. The initial TESEO data highlight the evolution of CAT, with new agents and thrombotic risk factors

Avoidable mortality from giving tranexamic acid to bleeding trauma patients: an estimation based on WHO mortality data, a systematic literature review and data from the CRASH-2 trial

BACKGROUND: The CRASH-2 trial showed that early administration of tranexamic acid (TXA) safely reduces mortality in bleeding in trauma patients. Based on data from the CRASH-2 trial, global mortality data and a systematic literature review, we estimated the number of premature deaths that might be averted every year worldwide through the use of TXA. METHODS: We used CRASH-2 trial data to examine the effect of TXA on death due to bleeding by geographical region. We used WHO mortality data (2008) and data from a systematic review of the literature to estimate the annual number of in-hospital trauma deaths due to bleeding. We then used the relative risk estimates from the CRASH-2 trial to estimate the number of premature deaths that could be averted if all hospitalised bleeding trauma patients received TXA within one hour of injury, and within three hours of injury. Sensitivity analyses were used to explore the effect of uncertainty in the parameter estimates and the assumptions made in the model. RESULTS: There is no evidence that the effect of TXA on death due to bleeding varies by geographical region (heterogeneity p = 0.70). Based on WHO data and our systematic literature review, we estimate that each year worldwide there are approximately 400,000 in-hospital trauma deaths due to bleeding. If patients received TXA within one hour of injury then approximately 128,000 (uncertainty range [UR] ≈ 72,000 to 172,000) deaths might be averted. If patients received TXA within three hours of injury then approximately 112,000 (UR ≈ 68,000 to 148,000) deaths might be averted. Country specific estimates show that the largest numbers of deaths averted would be in India and China. CONCLUSIONS: The use of TXA in the treatment of traumatic bleeding has the potential to prevent many premature deaths every year. A large proportion of the potential health gains are in low and middle income countries

The Nucleosome Remodeling and Deacetylase Complex NuRD Is Built from Preformed Catalytically Active Sub-modules

The nucleosome remodeling deacetylase (NuRD) complex is a highly conserved regulator of chromatin structure and transcription. Structural studies have shed light on this and other chromatin modifying machines, but much less is known about how they assemble and whether stable and functional sub-modules exist that retain enzymatic activity. Purification of the endogenous $\textit{Drosophila}$ NuRD complex shows that it consists of a stable core of subunits, while others, in particular the chromatin remodeler CHD4, associate transiently. To dissect the assembly and activity of NuRD, we systematically produced all possible combinations of different components using the MultiBac system, and determined their activity and biophysical properties. We carried out single-molecule imaging of CHD4 in live mouse embryonic stem cells, in the presence and absence of one of core components (MBD3), to show how the core deacetylase and chromatin-remodeling sub-modules associate $\textit{in vivo}$. Our experiments suggest a pathway for the assembly of NuRD $\textit{via}$ preformed and active sub-modules. These retain enzymatic activity and are present in both the nucleus and the cytosol, an outcome with important implications for understanding NuRD function.This work was supported by the European Commission Framework Program 7 integrated project 4DCellFate (contract no. 277899), the Medical Research Council (MR/ M010082/1, to E.D.L.), and the Wellcome Trust (to I.B. and B.H.)

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum