Characterization of cellular and molecular responses of human glioblastoma to Transforming Growth Factor-β signalling pathway inhibition

Glioblastoma Multiforme (GBM) is the most prevalent malignant brain tumour accounting for 60-70% of all gliomas. Improvements in survival over the past 100 years can be measured only in weeks, and current achieved median survival ranges only 12-15 months. A hallmark of this malignancy is the intrinsic resistance to current therapies. Numerous efforts using molecularly targeted therapeutics have not significantly changed the near uniform lethality of this disease. The TGF-β signalling pathway plays a key role in GBM. It is implicated in progression, infiltration, and chemo/radioresistance as well as in the maintenance of stem-like phenotype of GBM CSC. Several inhibitors of different elements and regulators of the TGF-β pathway have entered to clinical trials. Among them, P17 and P144 inhibitory peptides of the TGF-β pathway have been tested for the treatment of different diseases including tumours. We decided to analyse the therapeutic potential of P144 for the treatment of GBM. We found that P144 impaired in vitro cellular processes as proliferation, migration, invasiveness and tumorigenicity. Apoptosis and anoikis were significantly increased by P144. Additionally, P144 blocked the TGF-β protective effect against apoptosis. The inhibition of TGF-β signalling by P144 affected the self-renewal capacity of a putative CSC subpopulation in vitro. These results were confirmed by the analysis on Brain Tumour Initiating Cells (BTIC) isolated from human GBM biopsies. P144 decreased in vitro proliferation, migration, and self-renewal capacity of this subpopulation. The effect of P144 was impaired by hypoxia. However, the precise underlying mechanism of hypoxia on P144 must be elucidated. We confirm the inhibition of TGF-β signalling by P144 through SMAD2 phosphorylation blockade, the pivotal initiation event of the pathway, which was translated to a reduction of P-SMAD2 nuclear translocation. Both results suggested an in vitro regulation on the transcriptional target genes of the TGF-β pathway in GBM cell lines. Furthermore, we confirmed in vitro and in vivo, the upregulation of SMAD7 and the downregulation of SKI by P144 at transcriptional and translational levels. This observation strongly suggests the implication of these factors in the molecular mechanism triggered by P144. The therapeutic potential of P144 was analysed in a mouse subcutaneous tumour model. Despite that P144 impaired tumour growth and leaded to an increase in survival, negative contradictory results were obtained in the in vivo intracranial model. We can conclude that the therapeutic potential of P144 as a treatment of GBM is clear. However, previous to potential clinical development, further studies are required in order to confirm P144 effect over GBM in the brain environment, as well as to explore P144 therapeutic potential in combination with current (TMZ and/or radiation) and emerging molecular based therapies

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk

Dark sector searches with the CMS experiment

Astrophysical observations provide compelling evidence for gravitationally interacting dark matter in the universe that cannot be explained by the standard model of particle physics. The extraordinary amount of data from the CERN LHC presents a unique opportunity to shed light on the nature of dark matter at unprecedented collision energies. This Report comprehensively reviews the most recent searches with the CMS experiment for particles and interactions belonging to a dark sector and for dark-sector mediators. Models with invisible massive particles are probed by searches for signatures of missing transverse momentum recoiling against visible standard model particles. Searches for mediators are also conducted via fully visible final states. The results of these searches are compared with those obtained from direct-detection experiments. Searches for alternative scenarios predicting more complex dark sectors with multiple new particles and new forces are also presented. Many of these models include long-lived particles, which could manifest themselves with striking unconventional signatures with relatively small amounts of background. Searches for such particles are discussed and their impact on dark-sector scenarios is evaluated. Many results and interpretations have been newly obtained for this Report

The CMS statistical analysis and combination tool: COMBINE

This paper describes the COMBINE software package used for statistical analyses by the CMS Collaboration. The package, originally designed to perform searches for a Higgs boson and the combined analysis of those searches, has evolved to become the statistical analysis tool presently used in the majority of measurements and searches performed by the CMS Collaboration. It is not specific to the CMS experiment, and this paper is intended to serve as a reference for users outside of the CMS Collaboration, providing an outline of the most salient features and capabilities. Readers are provided with the possibility to run COMBINE and reproduce examples provided in this paper using a publicly available container image. Since the package is constantly evolving to meet the demands of ever-increasing data sets and analysis sophistication, this paper cannot cover all details of COMBINE. However, the online documentation referenced within this paper provides an up-to-date and complete user guide

Searches for pair-produced multijet resonances using data scouting in proton-proton collisions at s\sqrt{s} = 13 TeV

Searches for pair-produced multijet signatures using data corresponding to an integrated luminosity of 128 fb$^{-1}$ of proton-proton collisions at $\sqrt{s}$ = 13 TeV are presented. A data scouting technique is employed to record events with low jet scalar transverse momentum sum values. The electroweak production of particles predicted in $R$-parity violating supersymmetric models is probed for the first time with fully hadronic final states. This is the first search for prompt hadronically decaying mass-degenerate higgsinos, and extends current exclusions on $R$-parity violating top squarks and gluinos

Search for CPCP violation in D0^0→\to KS0^0_\mathrm{S}KS0^0_\mathrm{S} decays in proton-proton collisions at s\sqrt{s} = 13 TeV

A search is reported for charge-parity D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ violation in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ decays, using data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb$^{-1}$, which consists of about 10 billion events containing a pair of ẖadrons, nearly all of which decay to charm hadrons. The flavor of the neutral D meson is determined by the pion charge in the reconstructed decays D$^{*+}$$\to$ D$^0\pi^+$ and D$^{*-}$$\to$ D$^0\pi^-$. The D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ asymmetry in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ is measured to be $A_{CP}$( K$^0_\mathrm{S}$K$^0_\mathrm{S}$) = (6.2 $\pm$ 3.0 $\pm$ 0.2 $\pm$ 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of the D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry in the D$^0$ $\to$ K$^0_\mathrm{S}\pi^+\pi^-$ decay. This is the first D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state