Metformin and Everolimus: A Promising Combination for Neuroendocrine Tumors Treatment

Introduction: Treatment options for neuroendocrine tumors (NETs) are rarely curative, as NETs frequently show resistance to medical therapy. The use of everolimus, an mTOR inhibitor, is limited by the development of resistance, probably due to the activation of Akt signaling. In this context, the antidiabetic drug metformin is able to inhibit mTOR, providing a rationale for the use of metformin and everolimus in combination. Methods: We investigated the effects of the metformin and everolimus combination on NET cell proliferation, apoptosis, colony formation, cell viability, NET spheroids growth and the involvement of the Akt and mTOR pathways, and also developed everolimus-resistant NET cells to further study this combination. Results: Metformin and everolimus in combination are more effective than monotherapy in inhibiting pancreatic NET (PAN-NET) cell proliferation (-71% \ub1 13%, p < 0.0001 vs. basal), whereas no additive effects were observed on pulmonary neuroendocrine tumor (PNT) cell proliferation. The combinatorial treatment is more effective than monotherapy in inhibiting colony formation, cell viability, NET spheroids growth rate and mTOR phosphorylation in both NET cell lines. In a PAN-NET cell line, metformin did not affect Akt phosphorylation; conversely, it significantly decreased Akt phosphorylation in a PNT cell line. Using everolimus-resistant NET cells, we confirmed that metformin maintained its effects, acting by two different pathways: Akt-dependent or independent, depending on the cell type, with both leading to mTOR suppression. Conclusions: Considering the promising effects of the everolimus and metformin combination in NET cells, our results provide a rationale for its use in NET patients

Measurement of the CKM angle γγ in B±→DK±B^\pm\to D K^\pm and B±→Dπ±B^\pm \to D π^\pm decays with D→KS0h+h−D \to K_\mathrm S^0 h^+ h^-

A measurement of $CP$-violating observables is performed using the decays $B^\pm\to D K^\pm$ and $B^\pm\to D \pi^\pm$, where the $D$ meson is reconstructed in one of the self-conjugate three-body final states $K_{\mathrm S}\pi^+\pi^-$ and $K_{\mathrm S}K^+K^-$ (commonly denoted $K_{\mathrm S} h^+h^-$). The decays are analysed in bins of the $D$-decay phase space, leading to a measurement that is independent of the modelling of the $D$-decay amplitude. The observables are interpreted in terms of the CKM angle $\gamma$. Using a data sample corresponding to an integrated luminosity of $9\,\text{fb}^{-1}$ collected in proton-proton collisions at centre-of-mass energies of $7$, $8$, and $13\,\text{TeV}$ with the LHCb experiment, $\gamma$ is measured to be $\left(68.7^{+5.2}_{-5.1}\right)^\circ$. The hadronic parameters $r_B^{DK}$, $r_B^{D\pi}$, $\delta_B^{DK}$, and $\delta_B^{D\pi}$, which are the ratios and strong-phase differences of the suppressed and favoured $B^\pm$ decays, are also reported

Measurement of forward charged hadron flow harmonics in peripheral PbPb collisions at √sNN = 5.02 TeV with the LHCb detector

Flow harmonic coefficients, v n , which are the key to studying the hydrodynamics of the quark-gluon plasma (QGP) created in heavy-ion collisions, have been measured in various collision systems and kinematic regions and using various particle species. The study of flow harmonics in a wide pseudorapidity range is particularly valuable to understand the temperature dependence of the shear viscosity to entropy density ratio of the QGP. This paper presents the first LHCb results of the second- and the third-order flow harmonic coefficients of charged hadrons as a function of transverse momentum in the forward region, corresponding to pseudorapidities between 2.0 and 4.9, using the data collected from PbPb collisions in 2018 at a center-of-mass energy of 5.02 TeV . The coefficients measured using the two-particle angular correlation analysis method are smaller than the central-pseudorapidity measurements at ALICE and ATLAS from the same collision system but share similar features

Helium identification with LHCb

The identification of helium nuclei at LHCb is achieved using a method based on measurements of ionisation losses in the silicon sensors and timing measurements in the Outer Tracker drift tubes. The background from photon conversions is reduced using the RICH detectors and an isolation requirement. The method is developed using pp collision data at √(s) = 13 TeV recorded by the LHCb experiment in the years 2016 to 2018, corresponding to an integrated luminosity of 5.5 fb-1. A total of around 105 helium and antihelium candidates are identified with negligible background contamination. The helium identification efficiency is estimated to be approximately 50% with a corresponding background rejection rate of up to O(10^12). These results demonstrate the feasibility of a rich programme of measurements of QCD and astrophysics interest involving light nuclei

Curvature-bias corrections using a pseudomass method

Momentum measurements for very high momentum charged particles, such as muons from electroweak vector boson decays, are particularly susceptible to charge-dependent curvature biases that arise from misalignments of tracking detectors. Low momentum charged particles used in alignment procedures have limited sensitivity to coherent displacements of such detectors, and therefore are unable to fully constrain these misalignments to the precision necessary for studies of electroweak physics. Additional approaches are therefore required to understand and correct for these effects. In this paper the curvature biases present at the LHCb detector are studied using the pseudomass method in proton-proton collision data recorded at centre of mass energy √(s)=13 TeV during 2016, 2017 and 2018. The biases are determined using Z→μ + μ - decays in intervals defined by the data-taking period, magnet polarity and muon direction. Correcting for these biases, which are typically at the 10-4 GeV-1 level, improves the Z→μ + μ - mass resolution by roughly 18% and eliminates several pathological trends in the kinematic-dependence of the mean dimuon invariant mass

Study of the doubly charmed tetraquark T+cc

Quantum chromodynamics, the theory of the strong force, describes interactions of coloured quarks and gluons and the formation of hadronic matter. Conventional hadronic matter consists of baryons and mesons made of three quarks and quark-antiquark pairs, respectively. Particles with an alternative quark content are known as exotic states. Here a study is reported of an exotic narrow state in the D0D0π+ mass spectrum just below the D*+D0 mass threshold produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The state is consistent with the ground isoscalar T+cc tetraquark with a quark content of ccu⎯⎯⎯d⎯⎯⎯ and spin-parity quantum numbers JP = 1+. Study of the DD mass spectra disfavours interpretation of the resonance as the isovector state. The decay structure via intermediate off-shell D*+ mesons is consistent with the observed D0π+ mass distribution. To analyse the mass of the resonance and its coupling to the D*D system, a dedicated model is developed under the assumption of an isoscalar axial-vector T+cc state decaying to the D*D channel. Using this model, resonance parameters including the pole position, scattering length, effective range and compositeness are determined to reveal important information about the nature of the T+cc state. In addition, an unexpected dependence of the production rate on track multiplicity is observed

Motion compensated whole-heart coronary cardiovascular magnetic resonance angiography using focused navigation (fNAV).

Radial self-navigated (RSN) whole-heart coronary cardiovascular magnetic resonance angiography (CCMRA) is a free-breathing technique that estimates and corrects for respiratory motion. However, RSN has been limited to a 1D rigid correction which is often insufficient for patients with complex respiratory patterns. The goal of this work is therefore to improve the robustness and quality of 3D radial CCMRA by incorporating both 3D motion information and nonrigid intra-acquisition correction of the data into a framework called focused navigation (fNAV). We applied fNAV to 500 data sets from a numerical simulation, 22 healthy subjects, and 549 cardiac patients. In each of these cohorts we compared fNAV to RSN and respiratory resolved extradimensional golden-angle radial sparse parallel (XD-GRASP) reconstructions of the same data. Reconstruction times for each method were recorded. Motion estimate accuracy was measured as the correlation between fNAV and ground truth for simulations, and fNAV and image registration for in vivo data. Percent vessel sharpness was measured in all simulated data sets and healthy subjects, and a subset of patients. Finally, subjective image quality analysis was performed by a blinded expert reviewer who chose the best image for each in vivo data set and scored on a Likert scale 0-4 in a subset of patients by two reviewers in consensus. The reconstruction time for fNAV images was significantly higher than RSN (6.1 ± 2.1 min vs 1.4 ± 0.3, min, p < 0.025) but significantly lower than XD-GRASP (25.6 ± 7.1, min, p < 0.025). Overall, there is high correlation between the fNAV and reference displacement estimates across all data sets (0.73 ± 0.29). For simulated data, healthy subjects, and patients, fNAV lead to significantly sharper coronary arteries than all other reconstruction methods (p < 0.01). Finally, in a blinded evaluation by an expert reviewer fNAV was chosen as the best image in 444 out of 571 data sets (78%; p < 0.001) and consensus grades of fNAV images (2.6 ± 0.6) were significantly higher (p < 0.05) than uncorrected (1.7 ± 0.7), RSN (1.9 ± 0.6), and XD-GRASP (1.8 ± 0.8). fNAV is a promising technique for improving the quality of RSN free-breathing 3D whole-heart CCMRA. This novel approach to respiratory self-navigation can derive 3D nonrigid motion estimations from an acquired 1D signal yielding statistically significant improvement in image sharpness relative to 1D translational correction as well as XD-GRASP reconstructions. Further study of the diagnostic impact of this technique is therefore warranted to evaluate its full clinical utility

2D cine vs. 3D self-navigated free-breathing high-resolution whole heart cardiovascular magnetic resonance for aortic root measurements in congenital heart disease.

Cardiovascular magnetic resonance (CMR) is considered the method of choice for evaluation of aortic root dilatation in congenital heart disease. Usually, a cross-sectional 2D cine stack is acquired perpendicular to the vessel's axis. However, this method requires a considerable patient collaboration and precise planning of image planes. The present study compares a recently introduced 3D self-navigated free-breathing high-resolution whole heart CMR sequence (3D self nav) allowing a multiplanar retrospective reconstruction of the aortic root as an alternative to the 2D cine technique for determination of aortic root diameters. A total of 6 cusp-commissure (CuCo) and cusp-cusp (CuCu) enddiastolic diameters were measured by two observers on 2D cine and 3D self nav cross-sectional planes of the aortic root acquired on a 1.5 T CMR scanner. Asymmetry of the aortic root was evaluated by the ratio of the minimal to the maximum 3D self nav CuCu diameter. CuCu diameters were compared to standard transthoracic echocardiographic (TTE) aortic root diameters. Sixty-five exams in 58 patients (32 ± 15 years) were included. Typically, 2D cine and 3D self nav spatial resolution was 1.1-1.5 <sup>2</sup> × 4.5-7 mm and 0.9-1.15 <sup>3</sup> mm, respectively. 3D self nav yielded larger maximum diameters than 2D cine: CuCo 37.2 ± 6.4 vs. 36.2 ± 7.0 mm (p = 0.006), CuCu 39.7 ± 6.3 vs. 38.5 ± 6.5 mm (p < 0.001). CuCu diameters were significantly larger (2.3-3.9 mm, p < 0.001) than CuCo and TTE diameters on both 2D cine and 3D self nav. Intra- and interobserver variabilities were excellent for both techniques with bias of -0.5 to 1.0 mm. Intra-observer variability of the more experienced observer was better for 3D self nav (F-test p < 0.05). Aortic root asymmetry was more pronounced in patients with bicuspid aortic valve (BAV: 0.73 (interquartile (IQ) 0.69; 0.78) vs. 0.93 (IQ 0.9; 0.96), p < 0.001), which was associated to a larger difference of maximum CuCu to TTE diameters: 5.5 ± 3.3 vs. 3.3 ± 3.8 mm, p = 0.033. Both, the 3D self nav and 2D cine CMR techniques allow reliable determination of aortic root diameters. However, we propose to privilege the 3D self nav technique and measurement of CuCu diameters to avoid underestimation of the maximum diameter, particularly in patients with asymmetric aortic roots and/or BAV

Volumetric coronary endothelial function assessment: a feasibility study exploiting stack-of-stars 3D cine MRI and image-based respiratory self-gating.

Abnormal coronary endothelial function (CEF), manifesting as depressed vasoreactive responses to endothelial-specific stressors, occurs early in atherosclerosis, independently predicts cardiovascular events, and responds to cardioprotective interventions. CEF is spatially heterogeneous along a coronary artery in patients with atherosclerosis, and thus recently developed and tested non-invasive 2D MRI techniques to measure CEF may not capture the extent of changes in CEF in a given coronary artery. The purpose of this study was to develop and test the first volumetric coronary 3D MRI cine method for assessing CEF along the proximal and mid-coronary arteries with isotropic spatial resolution and in free-breathing. This approach, called 3D-Stars, combines a 6 min continuous, untriggered golden-angle stack-of-stars acquisition with a novel image-based respiratory self-gating method and cardiac and respiratory motion-resolved reconstruction. The proposed respiratory self-gating method agreed well with respiratory bellows and center-of-k-space methods. In healthy subjects, 3D-Stars vessel sharpness was non-significantly different from that by conventional 2D radial in proximal segments, albeit lower in mid-portions. Importantly, 3D-Stars detected normal vasodilatation of the right coronary artery in response to endothelial-dependent isometric handgrip stress in healthy subjects. Coronary artery cross-sectional areas measured using 3D-Stars were similar to those from 2D radial MRI when similar thresholding was used. In conclusion, 3D-Stars offers good image quality and shows feasibility for non-invasively studying vasoreactivity-related lumen area changes along the proximal coronary artery in 3D during free-breathing