Complejos de oro y compuestos polifenólicos como agentes antiproliferativos en el cáncer de colon: determinación de dianas terapéuticas y vías de muerte celular

En los últimos años la incidencia del cáncer se ha disparado y se prevé que estas cifras sigan aumentando a lo largo de las próximas décadas. Además, se trata de enfermedades muy agresivas que, en muchos casos, no cuentan con un tratamiento adecuado que permita eliminar las células tumorales con los menos efectos secundarios posibles. En concreto, el cáncer colorrectal no solo es uno de los más diagnosticados, con cerca de 2.000.000 de nuevos casos al año, sino que además presenta una alta tasa de mortalidad (la supervivencia general a 5 años es de en torno al 60%). Por lo tanto, es necesario encontrar nuevas terapias que permitan aumentar esa tasa de supervivencia.En la presente tesis se ha estudiado el potencial de diversos tipos de complejos de oro comopotenciales fármacos frente al cáncer de colon, así como la influencia que los diferentes ligandos pueden tener en la actividad anticancerígena de los mismos. En una segunda vertiente del estudio, se ha querido explorar las posibilidades de extractos vegetales ricos en compuestos polifenólicos como terapias anticancerígenas y como solución a un problema medioambiental de acumulación de residuos.En cuanto a los complejos de oro, se ha observado que complejos de oro(III) con ligandos tiolatoy ditiocarbamato exhiben poder antiproliferativo frente a células de cáncer de colon humanas (Caco-2). Por otro lado, una nueva familia de complejos de oro(I) con ligandos 1,3,5-Triaza-7- fosfaadamantano (PTA) alquiladas también presentaron poder citotóxico frente a células Caco- 2. Además, se observó que cuando las células incubadas con los complejos eran sometidas a un leve aumento de temperatura (hipertermia – 40 oC –) esta capacidad citotóxica se veía incrementada. Por último, se estudió la influencia de la coordinación de ligandos derivados de sulfonamidas a oro(I) en forma de ligandos del tipo ditiocarbamato, obteniendo de nuevo complejos metálicos con la capacidad de inhibir el crecimiento de las células Caco-2.Para analizar en profundidad la citotoxicidad de los complejos de oro se realizaron diversos estudios por citometría de flujo, obteniendo en todos los casos resultados similares. El tratamiento de células Caco-2 con los complejos lleva a la parada del ciclo celular y la despolarización de la membrana mitocondrial, lo que conduce en última instancia a la muertecelular por apoptosis.Además, el estudio de las posibles dianas intracelulares mostró que la mayoría de los complejos de oro analizados son capaces de inhibir la enzima tiorredoxina reductasa in vitro. Sin embargo,en el caso de los complejos de oro(III) con ligandos ditiocarbamato, la tiorredoxina reductasa nose veía afectada a nivel celular, siendo en estos casos la actividad del proteasoma la que se ve comprometida tras el tratamiento con dichos complejos. Por último, los complejos de oro(I) con ligandos ditiocarbamato derivados de bencenosulfonamidas mostraron la capacidad de inhibir la actividad de la anhidrasa carbónica IX purificada, además de la tiorredoxina reductasa.Con respecto a los extractos vegetales ricos en polifenoles, el estudio de un extracto de raspones de uva arrojó resultados prometedores como agente antiproliferativo frente a células humanas de cáncer colon (Caco-2) y de mama (MCF-7 y MDA-MB-231). En el caso de las tres líneas celulares el extracto rico en polifenoles es capaz de alterar el potencial de membrana y conducir a la apoptosis. Además, se observó que a concentraciones citotóxicas el extracto de raspones escapaz de aumentar el estrés oxidativo de las células cancerosas y modificar la actividad del proteasoma y la tiorredoxina reductasa.Incidence of cancer has growth alarmingly in the last decades and is expected to continue, or even increase this tendency in the following years. In addition, cancer is a very aggressive condition with inappropriate treatments, which hardly achieve cancer total regression or lead to several side effects. Colorectal carcinoma is specifically one of the most diagnosed cancers, with around 2.000.000 new cases every year. Moreover, survival rate in 5 years is lower than desired (near to 60%), which suggests the emergency of finding new therapies that allow to decrease that mortality. Within this thesis the anticarcinogenic effect of gold complexes against colon cancer has been studied, as well as the influence of different ligands on their anticancer properties. Secondly, the potential of polifenolic-riched plant extracts in cancer treatment was explored. The use of plant extracts would allow overcoming with a major environmental problem such as waste accumulation. Regarding gold complexes, new mixed thiolate-dithiocarbamate gold(III) derivatives displayed high antiproliferative effect against human colon cancer cells (Caco-2). On the other hand, a new family gold(I) complexes bearing alkylated 1,3,5-Triaza-7-phosphaadamantane ligands also proved cytotoxicity against Caco-2 cells. Moreover, this cytotoxic effect was enhanced by slightly increased temperature (hyperthermia - 40 oC). Finally, the influence of coordinating sulfonamide-derived dithiocarbamate ligands to gold(I) was analyzed. As previous gold derivatives, these complexes compromise Caco-2 cells survival, inhibiting normal cell proliferation. Deeper analysis of gold complexes cytotoxicity was carried by flow cytometry, which threw similar results for every studied complex. The treatment of Caco-2 cell with gold derivatives drives to cell cycle arrest and mitochondrial depolarization, which finally leads to apoptosis cell death. In addition, the study of potential intracellular targets showed that most analyzed gold complex inhibit thioredoxin reductase activity in vitro. However, gold(III) complexes bearing dithiocarbamate ligands do not compromise thioredoxin reductase activity in cells, whereas proteasome activity is inhibited. Finally, gold(I) complexes with sulfonamide-derived ligands exhibited the capacity to inhibit carbonic anhydrase IX activity, in addition to thioredoxin reductase. In relation to phenolic-rich plant extracts, the study of grape stem extracts exhibited promising results as antiproliferative agent against human colon (Caco-2) and breast (MCF-7 and MDA-MB-231) cells. In three tested cell lines, treatment with the extract rich in polyphenols disrupt mitochondrial membrane potential and lead to apoptosis. In addition, cytotoxic concentrations of grape stem extracts increase oxidative stress in cancerous cells and alter proteasome and thioredoxin reductase activities.<br /

Estudio de las propiedades anticancerígenas de complejos metálicos de oro con ligandos ditiocarbamato

El cáncer es en la actualidad uno de los trastornos más investigados debido a su alta incidencia y al desconocimiento que todavía existe acerca de su aparición y desarrollo. Dentro de los distintos tipos de tumores que el organismo humano puede desarrollar, el tercero con mayor incidencia a nivel mundial es el cáncer de colon. Los efectos secundarios que el uso de los tratamientos convencionales, la radioterapia y la quimioterapia, acarrean en el paciente, junto a su escasa efectividad, propicia la búsqueda de nuevos tratamientos. En esta línea aparecieron los complejos metálicos, entre los que se encuentran los complejos de oro(I) y de oro(III). En el presente trabajo se ensayó el efecto de cuatro complejos de oro(III) sobre la línea celular Caco-2/TC7 (células de carcinoma de colon humano) para determinar tanto su actividad citotóxica como las posibles dianas y vías de actuación. Se ha visto que todos los complejos estudiados son capaces de inducir la muerte celular en células anticancerígenas, aunque el complejo 4 carece de selectividad y también afecta a los enterocitos normales. La inducción de la necroptosis mediante la activación de proteínas como la quinasa RIP1, parece ser la causa del efecto citotóxico de estos complejos de oro(III). Por último, la enzima tiorredoxina reductasa se presenta como una de las dianas del complejo 2, que rompería la homeostasis redox en las células, aumentando los niveles de ROS y favoreciendo la muerte celular

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 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

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

Bose-Einstein correlations of charged hadrons in proton-proton collisions at s\sqrt s = 13 TeV

Bose-Einstein correlations of charged hadrons are measured over a broad multiplicity range, from a few particles up to about 250 reconstructed charged hadrons in proton-proton collisions at $\sqrt{s}$ = 13 TeV. The results are based on data collected using the CMS detector at the LHC during runs with a special low-pileup configuration. Three analysis techniques with different degrees of dependence on simulations are used to remove the non-Bose-Einstein background from the correlation functions. All three methods give consistent results. The measured lengths of homogeneity are studied as functions of particle multiplicity as well as average pair transverse momentum and mass. The results are compared with data from both CMS and ATLAS at $\sqrt{s}$ = 7 TeV, as well as with theoretical predictions.[graphic not available: see fulltext]Bose-Einstein correlations of charged hadrons are measured over a broad multiplicity range, from a few particles up to about 250 reconstructed charged hadrons in proton-proton collisions at $\sqrt{s} =$ 13 TeV. The results are based on data collected using the CMS detector at the LHC during runs with a special low-pileup configuration. Three analysis techniques with different degrees of dependence on simulations are used to remove the non-Bose-Einstein background from the correlation functions. All three methods give consistent results. The measured lengths of homogeneity are studied as functions of particle multiplicity as well as average pair transverse momentum and mass. The results are compared with data from both CMS and ATLAS at $\sqrt{s} =$ 7 TeV, as well as with theoretical predictions

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

Measurement of b jet shapes in proton-proton collisions at root s=5.02 TeV

We present the first study of charged-hadron production associated with jets originating from b quarks in proton-proton collisions at a center-of-mass energy of 5.02 TeV. The data sample used in this study was collected with the CMS detector at the CERN LHC and corresponds to an integrated luminosity of 27.4 pb(-1). To characterize the jet substructure, the differential jet shapes, defined as the normalized transverse momentum distribution of charged hadrons as a function of angular distance from the jet axis, are measured for b jets. In addition to the jet shapes, the per-jet yields of charged particles associated with b jets are also quantified, again as a function of the angular distance with respect to the jet axis. Extracted jet shape and particle yield distributions for b jets are compared with results for inclusive jets, as well as with the predictions from the pythia and herwig++ event generators.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| &lt; 0.03 at 95% confidence level. [Figure not available: see fulltext.