Estudo da regulação da angiogénese tumoral pelo H2O2 in vivo

Tese de mestrado. Biologia (Biologia Molecular e Genética). Universidade de Lisboa, Faculdade de Ciências, 2011A angiogénese é um processo muito importante na progressão tumoral, permitindo o aporte de oxigénio e nutrientes necessários para o crescimento do tumor. O H2O2 é uma espécie reactiva de oxigénio que está actualmente a atrair o interesse dos investigadores pela sua função na regulação de várias vias de sinalização, através da modulação proteica por oxidação. O facto de ter a sua produção elevada nas células tumorais e desempenhar importantes funções no potenciamento da sinalização pelo VEGF e na modulação da actividade de factores de transcrição e de outras proteínas, tornam esta molécula num alvo de estudo importante para a compreensão da angiogénese tumoral. Para tal, foi estabelecido um modelo de xenotransplante tumoral em embrião de peixezebra, que permitiu averiguar o efeito na angiogénese da modulação dos níveis do H2O2 nas células tumorais. Foi verificado que a prevenção da produção de H2O2 pelas células tumorais tem dois efeitos distintos e independentes no processo angiogénico: a diminuição do recrutamento vascular e a inibição da invasão vascular no tumor. Para além do efeito na angiogénese tumoral, a diminuição dos níveis de H2O2 nas células tumorais é capaz de inibir o recrutamento de macrófagos para o implante tumoral. Os resultados obtidos permitem concluir que o H2O2 influencia diferentes processos celulares essenciais na progressão tumoral. Foi também possível mostrar neste trabalho as vantagens do modelo de peixe-zebra para o estudo da função do H2O2 num contexto tumoral. Assim, o H2O2 apresenta-se como um importante sinalizador molecular e um promissor alvo terapêutico no tratamento do cancro.Tumor growth is allowed to advance through the process of neoangiogenesis, which allows the transport of the necessary nutrients and oxygen to the tumor. This process is induced by the tumor cells that produce pro-angiogenic factors, being VEGF one of the most important. It is known that H2O2, a reactive oxygen specie, has an important role in the regulation of signaling pathways by protein modulation. This molecule has the ability to enhance VEGF signaling and also modulates the activity of angiogenic related proteins and transcription factors. Hence, the understanding of the H2O2 modulation pathways will unravel new insights for the comprehension of tumor angiogenesis.In this work, a tumor xenograft model using zebrafish embryos was optimized in order to understand the effects of H2O2 levels produced by tumor cells in the neoangiogenesis process. It is shown here that low levels of H2O2 in tumor cells, inhibits independently two major cellular events in the angiogenic process: endothelial cell recruitment and vascular invasion of tumors. In addition to the effects on angiogenesis, H2O2 levels in tumor cells are also able to modulate macrophage attraction to the tumor. These results indicate that H2O2 produced by tumor cells modulate several cellular processes, which are essential for tumor progression, revealing this molecule as a promising therapeutic target for cancer

Search for non-resonant Higgs boson pair production in final states with leptons, taus, and photons in pp collisions at √s = 13 TeV with the ATLAS detector

A search is presented for non-resonant Higgs boson pair production, targeting the bbZZ, 4V (V = W or Z), V V τ τ , 4τ , γγV V and γγτ τ decay channels. Events are categorised based on the multiplicity of light charged leptons (electrons or muons), hadronically decaying tau leptons, and photons. The search is based on a data sample of proton-proton collisions at √s = 13 TeV recorded with the ATLAS detector during Run 2 of the Large Hadron Collider, corresponding to an integrated luminosity of 140 fb−1. No evidence of the signal is found and the observed (expected) upper limit on the cross-section for non-resonant Higgs boson pair production is determined to be 17 (11) times the Standard Model predicted cross-section at 95% confidence level under the background-only hypothesis. The observed (expected) constraints on the HHH coupling modifier, κλ, are determined to be −6.2 < κλ < 11.6 (−4.5 < κλ < 9.6) at 95% confidence level, assuming the Standard Model for the expected limits and that new physics would only affect κλ

Measurement of vector boson production cross sections and their ratios using pp collisions at √s = 13.6 TeV with the ATLAS detector

Abstract available from publisher's website

Beam-induced backgrounds measured in the ATLAS detector during local gas injection into the LHC beam vacuum

Inelastic beam-gas collisions at the Large Hadron Collider (LHC), within a few hundred metres of the ATLAS experiment, are known to give the dominant contribution to beam backgrounds. These are monitored by ATLAS with a dedicated Beam Conditions Monitor (BCM) and with the rate of fake jets in the calorimeters. These two methods are complementary since the BCM probes backgrounds just around the beam pipe while fake jets are observed at radii of up to several metres. In order to quantify the correlation between the residual gas density in the LHC beam vacuum and the experimental backgrounds recorded by ATLAS, several dedicated tests were performed during LHC Run 2. Local pressure bumps, with a gas density several orders of magnitude higher than during normal operation, were introduced at different locations. The changes of beam-related backgrounds, seen in ATLAS, are correlated with the local pressure variation. In addition the rates of beam-gas events are estimated from the pressure measurements and pressure bump profiles obtained from calculations. Using these rates, the efficiency of the ATLAS beam background monitors to detect beam-gas events is derived as a function of distance from the interaction point. These efficiencies and characteristic distributions of fake jets from the beam backgrounds are found to be in good agreement with results of beam-gas simulations performed with theFluka Monte Carlo programme

Search for heavy Majorana neutrinos in e±e± and e±μ± final states via WW scattering in pp collisions at √s = 13 TeV with the ATLAS detector

A search for heavy Majorana neutrinos in scattering of same-sign W boson pairs in proton–proton collisions at √s = 13 TeV at the LHC is reported. The dataset used corresponds to an integrated luminosity of 140 fb−1, collected with the ATLAS detector during 2015–2018. The search is performed in final states including a same-sign ee or eμ pair and at least two jets with large invariant mass and a large rapidity difference. No significant excess of events with respect to the Standard Model background predictions is observed. The results are interpreted in a benchmark scenario of the Phenomenological Type-I Seesaw model. New constraints are set on the values of the |VeN|2 and |VeN V*μN| parameters for heavy Majorana neutrino masses between 50 GeV and 20 TeV, where VℓN is the matrix element describing the mixing of the heavy Majorana neutrino mass eigenstate with the Standard Model neutrino of flavour ℓ = e, μ. The sensitivity to the Weinberg operator is investigated and constraints on the effective ee and eμ Majorana neutrino masses are reported. The statistical combination of the ee and eμ channels with the previously published μμ channel is performed

Search for dark mesons decaying to top and bottom quarks in proton-proton collisions at √s = 13 TeV with the ATLAS detector

A search for dark mesons originating from strongly-coupled, SU(2) dark favor symmetry conserving models and decaying gaugephobically to pure Standard Model final states containing top and bottom quarks is presented. The search targets fully hadronic final states and final states with exactly one electron or muon and multiple jets. The analyzed data sample corresponds to an integrated luminosity of 140 fb−1 of proton-proton collisions collected at √s = 13 TeV with the ATLAS detector at the Large Hadron Collider. No significant excess over the Standard Model background expectation is observed and the results are used to set the first direct constraints on this type of model. The two-dimensional signal space of dark pion masses mπD and dark rho-meson masses mρD is scanned. For mπD /mρD = 0.45, dark pions with masses mπD < 940 GeV are excluded at the 95% CL, while for mπD /mρD = 0.25 masses mπD < 740 GeV are excluded

Combination of searches for Higgs boson decays into a photon and a massless dark photon using pp collisions at √s = 13 TeV with the ATLAS detector

A combination of searches for Higgs boson decays into a visible photon and a massless dark photon (H → γγd) is presented using 139 fb−1 of proton-proton collision data at a centre-of-mass energy of √s = 13 TeV recorded by the ATLAS detector at the Large Hadron Collider. The observed (expected) 95% confidence level upper limit on the Standard Model Higgs boson decay branching ratio is determined to be B(H → γγd) < 1.3% (1.5)%. The search is also sensitive to higher-mass Higgs bosons decaying into the same final state. The observed (expected) 95% confidence level limit on the cross-section times branching ratio ranges from 16 fb (20 fb) for mH = 400 GeV to 1.0 fb (1.5 fb) for mH = 3 TeV. Results are also interpreted in the context of a minimal simplified model

Calibration of a soft secondary vertex tagger using proton-proton collisions at √s = 13 TeV with the ATLAS detector

Several processes studied by the ATLAS experiment at the Large Hadron Collider produce low-momentum b-flavored hadrons in the final state. This paper describes the calibration of a dedicated tagging algorithm that identifies b-flavored hadrons outside of hadronic jets by reconstructing the soft secondary vertices originating from their decays. The calibration is based on a proton-proton collision dataset at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 140  fb−1. Scale factors used to correct the algorithm’s performance in simulated events are extracted for the b-tagging efficiency and the mistag rate of the algorithm using a data sample enriched in tt¯ events. Several orthogonal measurement regions are defined, binned as a function of the multiplicities of soft secondary vertices and jets containing a b-flavored hadron in the event. The mistag rate scale factors are estimated separately for events with low and high average numbers of interactions per bunch crossing. The results, which are derived from events with low missing transverse momentum, are successfully validated in a phase space characterized by high missing transverse momentum and therefore are applicable to new physics searches carried out in either phase space regime

Measurement of single top-quark production in association with a W boson in pp collisions at √s = 13 TeV with the ATLAS detector

The inclusive cross section for the production of a single top quark in association with a W boson is measured using 140 fb−1 of proton-proton collision data collected with the ATLAS detector at √s = 13 TeV. Events containing two charged leptons and at least one jet identified as originating from a b-quark are selected. A multivariate discriminant is constructed to separate the tW signal from the t¯t background. The cross section is extracted using a profile likelihood fit to the signal and control regions and it is measured to be σtW = 75+15 −14 pb, in good agreement with the Standard Model prediction. The measured cross section is used to extract a value for the left-handed form factor at the Wtb vertex times the Cabibbo-Kobayashi-Maskawa matrix element |fLVVtb| of 0.97 0.10