Cancer associated fibroblasts predict for poor outcome and promote periostin-dependent invasion in oesophageal adenocarcinoma

Interactions between cancer cells and cancer-associated fibroblasts (CAF) play an important role in tumour development and progression. In this study we investigated the functional role of CAF in oesophageal adenocarcinoma (EAC). We used immunochemistry to analyse a cohort of EAC patients (183 patients) for CAF markers related to disease mortality. We characterized CAF and normal oesophageal fibroblasts (NOF) using western blotting, immunofluorescence and gel contraction. Transwell assays, 3-D organotypic culture and xenograft models were used to examine effects on EAC cell function, and dissect molecular mechanisms regulating invasion. Most EAC (93%) contained CAF with a myofibroblastic (?-SMA-positive) phenotype, which correlated significantly with poor survival (p?=?0.016; HR 7. 1 (1.7-29.4). Primary CAF, isolated from EAC, have a contractile, myofibroblastic phenotype, and promote EAC cell invasion in vitro (Transwell assays, p?=?<0.05; organotypic culture, p?<?0.001) and in vivo (p?=?<0.05). In vitro, this pro-invasive effect is modulated through the matricellular protein periostin. Periostin is secreted by CAF, and acts as a ligand for EAC cell integrins ?v?3 and ?v?5, promoting activation of the PI3kinase/Akt pathway. In patient samples, periostin expression at the tumour cell/stromal interface correlates with poor overall and disease-free survival. Our study highlights the importance of the tumour stroma in EAC progression. Paracrine interaction between CAF-secreted periostin and EAC-expressed integrins results in PI3 kinase/Akt activation and increased tumour cell invasion. Most EAC contain a myofibroblastic CAF-rich stroma; this may explain the aggressive, highly infiltrative nature of the disease, and suggests that stromal targeting may produce therapeutic benefit in EAC patient

HPV, tumour metabolism and novel target identification in head and neck squamous cell carcinoma

Background Metabolic changes in tumour cells are used in clinical imaging and may provide potential therapeutic targets. Human papillomavirus (HPV) status is important in classifying head and neck cancers (HNSCC), identifying a distinct clinical phenotype; metabolic differences between these HNSCC subtypes remain poorly understood. Methods We used RNA sequencing to classify the metabolic expression profiles of HPV+ve and HPV−ve HNSCC, performed a meta-analysis on FDG-PET imaging characteristics and correlated results with in vitro extracellular flux analysis of HPV−ve and HPV+ve HNSCC cell lines. The monocarboxylic acid transporter-1 (MCT1) was identified as a potential metabolic target and tested in functional assays. Results Specific metabolic profiles were associated with HPV status, not limited to carbohydrate metabolism. There was dominance of all energy pathways in HPV-negative disease, with elevated expression of genes associated with glycolysis and oxidative phosphorylation. In vitro analysis confirmed comparative increased rates of oxidative phosphorylation and glycolysis in HPV-negative cell lines. PET SUV(max) scores however were unable to reliably differentiate between HPV-positive and HPV-negative tumours. MCT1 expression was significantly increased in HPV-negative tumours, and inhibition suppressed tumour cell invasion, colony formation and promoted radiosensitivity. Conclusion HPV-positive and negative HNSCC have different metabolic profiles which may have potential therapeutic applications

Search for long-lived particles decaying to e±μ∓νe^\pm \mu^\mp \nu

International audienceLong-lived particles decaying to ${e ^\pm } {\mu ^\mp } {\nu }$, with masses between 7 and $50 \,\text {GeV/}c^2$ and lifetimes between 2 and $50 \,\text {ps}$, are searched for by looking at displaced vertices containing electrons and muons of opposite charges. The search is performed using $5.4 \,\text {fb} ^{-1}$ of $p p$ collisions collected with the LHCb detector at a centre-of-mass energy of $\sqrt{s} = 13 \,\text {TeV}$. Three mechanisms of production of long-lived particles are considered: the direct pair production from quark interactions, the pair production from the decay of a Standard-Model-like Higgs boson with a mass of $125 \,\text {GeV/}c^2$, and the charged current production from an on-shell $W$ boson with an additional lepton. No evidence of these long-lived states is obtained and upper limits on the production cross-section times branching fraction are set on the different production modes

Observation of Multiplicity Dependent Prompt χc1(3872)\chi_{c1}(3872) and ψ(2S)\psi(2S) Production in pppp Collisions

The production of $χ_{c1}$(3872) and $ψ$(2S) hadrons is studied as a function of charged particle multiplicity in pp collisions at a center-of-mass energy of 8 TeV, corresponding to an integrated luminosity of 2 fb-1. For both states, the fraction that is produced promptly at the collision vertex is found to decrease as charged particle multiplicity increases. The ratio of $χ_{c1}$(3872) to $ψ$(2S) cross sections for promptly produced particles is also found to decrease with multiplicity, while no significant dependence on multiplicity is observed for the equivalent ratio of particles produced away from the collision vertex in b-hadron decays. This behavior is consistent with a calculation that models the $χ_{c1}$(3872) structure as a compact tetraquark. Comparisons with model calculations and implications for the binding energy of the $χ_{c1}$(3872) state are discussed

Measurement of the charm mixing parameter yCP−yCPKπy_{CP} - y_{CP}^{K\pi} using two-body D0D^0 meson decays

International audienceA measurement of the ratios of the effective decay widths of D0→π-π+ and D0→K-K+ decays over that of D0→K-π+ decays is performed with the LHCb experiment using proton–proton collisions at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 6  fb-1. These observables give access to the charm mixing parameters yCPππ-yCPKπ and yCPKK-yCPKπ, and are measured as yCPππ-yCPKπ=(6.57±0.53±0.16)×10-3, yCPKK-yCPKπ=(7.08±0.30±0.14)×10-3, where the first uncertainties are statistical and the second systematic. The combination of the two measurements is yCP-yCPKπ=(6.96±0.26±0.13)×10-3, which is four times more precise than the previous world average

First observation of the decay Λb0→ηc(1S)pK−\Lambda_b^0 \to \eta_c(1S) p K^-

International audienceThe decay Λb0→ηc(1S)pK- is observed for the first time using a data sample of proton-proton collisions, corresponding to an integrated luminosity of 5.5  fb-1, collected with the LHCb experiment at a center-of-mass energy of 13 TeV. The branching fraction of the decay is measured, using the Λb0→J/ψpK- decay as a normalization mode, to be B(Λb0→ηc(1S)pK-)=(1.06±0.16±0.06-0.19+0.22)×10-4, where the quoted uncertainties are statistical, systematic and due to external inputs, respectively. A study of the ηc(1S)p mass spectrum is performed to search for the Pc(4312)+ pentaquark state. No evidence is observed and an upper limit of B(Λb0→Pc(4312)+K-)×B(Pc(4312)+→ηc(1S)p)B(Λb0→ηc(1S)pK-)<0.24 is obtained at the 95% confidence level

Measurement of χc1_{c1}(3872) production in proton-proton collisions at s \sqrt{s} = 8 and 13 TeV

International audienceThe production cross-section of the χ$_{c1}$(3872) state relative to the ψ(2S) meson is measured using proton-proton collision data collected with the LHCb experiment at centre-of-mass energies of $\sqrt{s}$ = 8 and 13 TeV, corresponding to integrated luminosities of 2.0 and 5.4 fb$^{−1}$, respectively. The two mesons are reconstructed in the J/ψπ$^{+}$π$^{−}$ final state. The ratios of the prompt and nonprompt χ$_{c1}$(3872) to ψ(2S) production cross-sections are measured as a function of transverse momentum, p$_{T}$, and rapidity, y, of the χ$_{c1}$(3872) and ψ(2S) states, in the kinematic range 4 < p$_{T}$< 20 GeV/c and 2.0 < y < 4.5. The prompt ratio is found to increase with p$_{T}$, independently of y. For the prompt component, the double ratio of the χ$_{c1}$(3872) and ψ(2S) production cross-sections between 13 and 8 TeV is observed to be consistent with unity, independent of p$_{T}$ and centre-of-mass energy.[graphic not available: see fulltext