Metabolismo y funcionalidad de HDL en un modelo murino (db/db) de diabesidad y efectos de la sobreexpresión de apolipoproteína A-I humana /

Numerosos estudios experimentales revelan una relación causal entre HDL y el riesgo de arteriosclerosis; de ahí, el interés en el desarrollo de diferentes estrategias basadas en la hiperexpresión de su principal apolipoproteína, (apo)A-I, para su prevención y tratamiento. Datos previos en humanos y modelos experimentales sugieren que las propiedades antiaterogénicas de las HDL se encuentran alteradas en obesidad y diabetes. El presente trabajo se centró en el estudio de las propiedades antiaterogénicas más importantes atribuidas a las HDL (ie, transporte reverso de colesterol específico de macrófagos in vivo -TRC-m-, y actividad antioxidante y antiinflamatoria) en un modelo animal de obesidad, el ratón db/db, y el impacto de la sobreexpresión de apoA-I humana (hA-I) sobre dichas propiedades. Los ratones db/db presentaron un aumento en los niveles plasmáticos de colesterol, principalmente debido a su aumento en HDL. El análisis cuantitativo y cualitativo de HDL reveló alteraciones en su tamaño y composición, y su catabolismo se encontró disminuido. Los estudios metabólicos en ratones db/db también revelaron una acumulación hepática del colesterol transportado por HDL y una eliminación de colesterol fecal disminuida, lo que se asoció con una disminución en la expresión génica de los transportadores de colesterol (ie, Abcg5 y Abcg8) y de ácidos biliares (ie, Bsep). Además de Abcg5 y Abcg8, la expresión de otras dianas moleculares de LXR también se encontró disminuida, sugiriendo que esta vía de señalización estaría comprometida en estos ratones. El análisis del TRC-m arrojó resultados similares a los alcanzados en la evaluación del metabolismo de HDL. La activación de LXR contribuyó a rescatar parcialmente el TRC-m en los ratones db/db, en concomitancia con un aumento en la expresión hepática de Abcg5 y Abcg8. Otras de las funciones ateroprotectoras más importantes de HDL analizadas ex vivo (ie, capacidad antioxidante y antiinflamatoria) también se encontraron alteradas en estos ratones. La sobreexpresión de hA-I en ratones transgénicos y en db/db (ie, db/db-hA-I) resultó en un aumento de los niveles plasmáticos de HDL y en cambios en su composición. También aumentó el TRC-m, en parte debido a un aumento combinado en la capacidad del plasma en promover el eflujo de colesterol desde macrófagos y su eliminación fecal, lo que coincidió con un restablecimiento de la expresión génica de los transportadores Abcg5 y Abcg8, principalmente involucrados en regular el tráfico de colesterol de hígado a heces. Sin embargo, dicho aumento no previno, incluso aumentó la esteatosis hepática en ratones db/db-hA-I en comparación con los ratones db/db. Por otro lado, aunque no se observaron cambios en la capacidad de HDL de los ratones db/db-hA-I de proteger de la oxidación a LDL, la resistencia de sus HDL a ser oxidadas sí aumentó, así como su capacidad antiinflamatoria. En conclusión, las principales propiedades funcionales ateroprotectoras de las HDL se encontraron comprometidas en el ratón db/db, principalmente debido a alteraciones en su composición y metabolismo. Aunque la presencia de cantidades elevadas de hA-I en este modelo experimental de diabesidad resultó en una mejora del TRC-m y en la capacidad antiinflamatoria de sus HDL, ello también se asoció al empeoramiento de otras alteraciones patológicas ya existentes, como la esteatosis hepática.A large body of experimental evidences reveals a causal inverse relationship between HDL and the risk of atherosclerostic vascular diseases. The demonstration that HDL and, its main apolipoprotein, apoA-I, exhibit favorable antiatherogenic actions has led to the development of different HDL-based strategies, such as that provided by the hyperexpression of apoA-I, for the prevention and treatment of atherosclerosis. Previous data in both humans and experimental models suggest that the antiatherogenic properties of HDL are impaired in obesity and diabetes. In this context, the main aims of the present work were to evaluate the most important anti-atherogenic properties attributed to HDL (ie, macrophage-specific reverse cholesterol transport in vivo -TRC-m-, and its anti-oxidant and anti-inflammatory activities ex vivo) in an animal model of diabesity, the db/db mouse, and the impact of overexpression of human apoA-I (hA-I) on these properties. The db/db mice showed an increase in their plasma levels of cholesterol, mainly attributed to elevated plasma levels of HDL. The quantitative and qualitative analysis of these lipoproteins revealed alterations in both their size and composition. The HDL from db/db were poorly catabolized compared with those from control mice. Metabolic studies also revealed that the HDL-related radiolabel was found to accumulate in the liver of the db/db mice, whereas the radiolabel reaching the feces was reduced compared with that of control mice. Notably, the latter finding was found further associated with a decreased expression in both the Abcg5 and Abcg8, and Bsep involved in the cholesterol and bile acid trafficking into bile, respectively. In addition to Abcg5 and Abcg8, the expression of other molecular targets of LXR was also reduced in the liver of db/db mice, suggesting that this signaling pathway could be compromised in these mice. Similar data were obtained after the evaluation of TRC-m in this model. Induction of LXR partially rescued the TRC-m in db/db mice, being the latter associated with a concomitant increase in the hepatic expression of Abcg5 and Abcg8. The other two most important atheroprotective functions attributed to HDL (ie, its anti-oxidant and anti-inflammatory capacity) were also found compromised in the db/db mice. The overexpression of hA-I in transgenic and in db/db mice (ie, db/db-hA-I) produced a striking elevation in the plasma levels of HDL in this model and in changes in the composition of their HDL. The TRC-m was also stimulated in this animal model, partly due to the combined increase in the capacity of plasma to promote cholesterol efflux from macrophages and cholesterol trafficking from the liver to feces, which coincided with a restoration of the hepatic expression of Abcg5 and Abcg8, two transporters mainly involved in modulating this process. However, such increase did not prevent, even exacerbated the hepatic steatosis in db/db-hA-I compared with db/db mice. Furthermore, the overexpression of hA-I in the db/db mice did not significantly improve the ability of their HDL to prevent LDL oxidation ex vivo, despite being less prone to oxidation than those from db/db mice, but significantly enhanced their anti-inflammatory capacity, being the latter mainly attributed to the presence of hA-I in their HDL. In conclusion, the main atheroprotective properties of HDL were hampered in the db/db mice, primarily due to alterations in their composition and metabolism. Furthermore, although the presence of hA-I in this experimental model of diabesity displayed a favorable impact on the TRC-m and improved the anti-inflammatory properties of their HDL, it also worsened other existing pathological alterations, such as hepatic steatosis

Characteristics and patterns of care of endometrial cancer before and during COVID-19 pandemic

Objective: Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. Methods: This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. Results: Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). Conclusion: Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic

Practice patterns and 90-day treatment-related morbidity in early-stage cervical cancer

To evaluate the impact of the Laparoscopic Approach to Cervical Cancer (LACC) Trial on patterns of care and surgery-related morbidity in early-stage cervical cancer

Measurement of t(t)over-bar normalised multi-differential cross sections in pp collisions at root s=13 TeV, and simultaneous determination of the strong coupling strength, top quark pole mass, and parton distribution functions

Peer reviewe

An embedding technique to determine ττ backgrounds in proton-proton collision data

An embedding technique is presented to estimate standard model tau tau backgrounds from data with minimal simulation input. In the data, the muons are removed from reconstructed mu mu events and replaced with simulated tau leptons with the same kinematic properties. In this way, a set of hybrid events is obtained that does not rely on simulation except for the decay of the tau leptons. The challenges in describing the underlying event or the production of associated jets in the simulation are avoided. The technique described in this paper was developed for CMS. Its validation and the inherent uncertainties are also discussed. The demonstration of the performance of the technique is based on a sample of proton-proton collisions collected by CMS in 2017 at root s = 13 TeV corresponding to an integrated luminosity of 41.5 fb(-1).Peer reviewe

Measurement of the Splitting Function in &ITpp &ITand Pb-Pb Collisions at root&ITsNN&IT=5.02 TeV

Data from heavy ion collisions suggest that the evolution of a parton shower is modified by interactions with the color charges in the dense partonic medium created in these collisions, but it is not known where in the shower evolution the modifications occur. The momentum ratio of the two leading partons, resolved as subjets, provides information about the parton shower evolution. This substructure observable, known as the splitting function, reflects the process of a parton splitting into two other partons and has been measured for jets with transverse momentum between 140 and 500 GeV, in pp and PbPb collisions at a center-of-mass energy of 5.02 TeV per nucleon pair. In central PbPb collisions, the splitting function indicates a more unbalanced momentum ratio, compared to peripheral PbPb and pp collisions.. The measurements are compared to various predictions from event generators and analytical calculations.Peer reviewe

Measurement of nuclear modification factors of gamma(1S)), gamma(2S), and gamma(3S) mesons in PbPb collisions at root s(NN)=5.02 TeV

The cross sections for ϒ(1S), ϒ(2S), and ϒ(3S) production in lead-lead (PbPb) and proton-proton (pp) collisions at √sNN = 5.02 TeV have been measured using the CMS detector at the LHC. The nuclear modification factors, RAA, derived from the PbPb-to-pp ratio of yields for each state, are studied as functions of meson rapidity and transverse momentum, as well as PbPb collision centrality. The yields of all three states are found to be significantly suppressed, and compatible with a sequential ordering of the suppression, RAA(ϒ(1S)) > RAA(ϒ(2S)) > RAA(ϒ(3S)). The suppression of ϒ(1S) is larger than that seen at √sNN = 2.76 TeV, although the two are compatible within uncertainties. The upper limit on the RAA of ϒ(3S) integrated over pT, rapidity and centrality is 0.096 at 95% confidence level, which is the strongest suppression observed for a quarkonium state in heavy ion collisions to date. © 2019 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP3.Peer reviewe

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| < 0.03 at 95% confidence level. [Figure not available: see fulltext.

Electroweak production of two jets in association with a Z boson in proton-proton collisions root s =13 TeV

A measurement of the electroweak (EW) production of two jets in association with a Z boson in proton-proton collisions at root s = 13 TeV is presented, based on data recorded in 2016 by the CMS experiment at the LHC corresponding to an integrated luminosity of 35.9 fb(-1). The measurement is performed in the lljj final state with l including electrons and muons, and the jets j corresponding to the quarks produced in the hard interaction. The measured cross section in a kinematic region defined by invariant masses m(ll) > 50 GeV, m(jj) > 120 GeV, and transverse momenta P-Tj > 25 GeV is sigma(EW) (lljj) = 534 +/- 20 (stat) fb (syst) fb, in agreement with leading-order standard model predictions. The final state is also used to perform a search for anomalous trilinear gauge couplings. No evidence is found and limits on anomalous trilinear gauge couplings associated with dimension-six operators are given in the framework of an effective field theory. The corresponding 95% confidence level intervals are -2.6 <cwww/Lambda(2) <2.6 TeV-2 and -8.4 <cw/Lambda(2) <10.1 TeV-2. The additional jet activity of events in a signal-enriched region is also studied, and the measurements are in agreement with predictions.Peer reviewe