Polimorfismo dei geni GSTP1, NQO1 e MDR1 e risposta alla chemioterapia nel trattamento del Mieloma Multiplo.

Il Mieloma Multiplo (MM) è una neoplasia con un’incidenza annua è di tre nuovi casi per 100.000 abitanti, mentre l’età media di insorgenza è di 70 anni, con una prevalenza nel sesso maschile. La prognosi dei pazienti di MM è piuttosto variabile e la sopravvivenza oscilla da 20 a 60 mesi. La terapia varia a secondo dello stadio clinico della malattia, ma uno dei regimi maggiormente usati è denominato DAV o VAD-like (dal nome dei farmaci impiegati, che sono vincristina, adriblastina e desametasone), che produce una buona risposta, senza danneggiare le cellule sane del midollo osseo, che sono destinate all’autotrapianto. Tuttavia una discreta percentuale di pazienti risulta refrattario alle dosi standard, e possono manifestare effetti collaterali, anche molto gravi. La variabilità interindividuale nella risposta clinica e nella sensibilità alla tossicità del farmaco, comune a molti regimi chemioterapici, può essere associata ad alterazioni genetiche, tra cui alcune mutazioni puntiformi (SNPs) in grado di alterare i livelli delle proteine coinvolte nel meccanismo d’azione del farmaco o nella sua biotrasformazione. La relazione tra la risposta alla chemioterapia e il genotipo del paziente può fornire utili informazioni che possono essere usate per predire l’efficacia de trattamento e/o la tossicità. Lo scopo del presente lavoro di tesi è di valutare la risposta individuale alla terapia DAV, in pazienti affetti da MM, in relazione al polimorfismo genetico di due enzimi metabolici Glutatione-S-Trasferasi-P1 (GSTP1 105Val) e NAD(P)H-Chinone:Ossidoreduttasi (NQO1 ProSer187) e del trasportatore ABCB1 (C3435T). Il GSTP1 appartiene alla famiglia delle Glutatione-S-Transferasi, un gruppo di enzimi della fase II di detossificazione, attraverso la coniugazione con il glutatione, di numerosi xenobiotici e chemioterapici. La variante GSTP1 105Val è associata ad una bassa stabilità termica ed ad una alterata attività catalitica substrato-specifica rispetto all’allele selvatico. Il gene NQO1 codifica per la NAD(P)H-Chinone:Ossidoreduttasi, un flavoenzima citosolico di fase I nel metabolismo degli xenobiotici e la sua variante 187Ser è associata ad una perdita di attività catalitica. Il gene MDR1 (o ABCB1) codifica per la glicoproteina-P (gp-P), un membro della superfamiglia dei trasportatori di membrana (ABC). La gp-P è coinvolta nel trasporto attivo di un ampio numero di molecole anfipatiche attraverso le membrane lipidiche. Il principale ruolo fisiologico è di protezione della cellula, e quindi dell’organismo, contro gli xenobiotici compresi i farmaci, come ad esempio le antracicline e gli alcaloidi della vinca. Il polimorfismo C3435T di MDR1 è la sola variante che è stata associata ad un’espressione alterata della proteina in vari tessuti e, generalmente, risulta in una diminuzione dei livelli di espressione. Il gruppo di pazienti reclutati prevalentemente dall’U.O. di Ematologia dell’Università Pisana, con la collaborazione delle U.O. di Parma e Reggio Calabria, è composto da 115 individui affetti da MM e sottoposti a regime DAV. Dei partecipanti allo studio sono state raccolte le informazioni sulle variabili demografiche (età, sesso) e cliniche (diagnosi, trattamento e follow-up) e campioni di sangue, da cui è stato estratto il DNA per l’analisi del genotipo con la metodica Taqman. L’analisi del genotipo non ha messo in evidenza alcun effetto significativo per i polimorfismi di NQO1 e MDR1 in relazione alla risposta alla chemioterapia, al trapianto e alla sopravvivenza a 30 mesi. Mentre la variante GSTP1 105Val risulta statisticamente associata con un esito peggiore della chemioterapia di induzione, ma non ha effetto sulla sopravvivenza. Questo risultato indica che GSTP1 potrebbe essere un "marker predittivo" della risposta a DAV nel trattamento del Mieloma Multiplo

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1(hi) effector CD8(+) T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8(+) T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1(hi) effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8(+) T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8(+) T cells

Vibro-acoustical performance of rib stiffened composite panels with embedded viscoelastic layers

LAUREA MAGISTRALEIn questa tesi viene presentato lo studio, attraverso metodi numerici, dell’effetto dei trattamenti viscoelastici sulla prestazione vibroacustica di pannelli irrigiditi in composito. L’interesse della ricerca si colloca nell’ambito della riduzione del rumore trasmesso all’interno della cabina di un aereoplano. Per calcolare le proprietà di massa, rigidezza e smorzamento di pannelli in materiale composito con incorporati trattamenti viscoelastici è stata sviluppata una apposita metodologia che si avvale della teoria classsica della laminazione (CLT) e delle equazioni di Ross, Kerwin e Ungar. La procedura viene validata sia numericamente sia attraverso il confronto con risultati sperimentali. Uno studio di sensitività delle prestazioni del laminato con trattamento viene eseguito variando i parametri di progetto e la temperatura operativa. Il coefficiente di perdita di trasmissione del rumore viene valutato al variare dei parametri di progetto dei trattamenti viscoelastici utilizzati. La simulazione numerica è svolta usando un modello vibroacustico agli elementi finiti sviluppato in MSC Nastran. Inoltre, i risultati vibroacustici sono correlati ai risultati di analisi di risposta in frequenza della sola struttura.This work describes the numerical evaluation of vibro-acoustic performance of rib-stiffened composite panels with embedded viscoelastic treatments. The interest of this research lies primarily in the context of the aircraft interior noise reduction. A procedure is developed to compute equivalent mass, stiffness and damping properties of composite laminates with damping treatments taking into account the frequency variation of viscoelastic materials properties. The procedure relies on the Classical Lamination Theory and Ross-Kerwin-Ungar equations and is validated both numerically and experimentally. A sensitivity study of the system performances is performed with design parameters and operative temperature variation. The sound transmission loss coefficients of rib-stiffened composite panels is evaluated numerically with the design parameters variation of the embedded viscoelastic treatments. The numerical simulation is carried out using a vibro-acoustical FE model developed in MSC Nastran. In addition, vibro-acoustical results are correlated with frequency response analysis results of an only-structural model

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Search for squarks and gluinos with the ATLAS detector in final states with jets and missing transverse momentum using √s=8 TeV proton-proton collision data

A search for squarks and gluinos in final states containing high-p T jets, missing transverse momentum and no electrons or muons is presented. The data were recorded in 2012 by the ATLAS experiment in s√=8 TeV proton-proton collisions at the Large Hadron Collider, with a total integrated luminosity of 20.3 fb−1. Results are interpreted in a variety of simplified and specific supersymmetry-breaking models assuming that R-parity is conserved and that the lightest neutralino is the lightest supersymmetric particle. An exclusion limit at the 95% confidence level on the mass of the gluino is set at 1330 GeV for a simplified model incorporating only a gluino and the lightest neutralino. For a simplified model involving the strong production of first- and second-generation squarks, squark masses below 850 GeV (440 GeV) are excluded for a massless lightest neutralino, assuming mass degenerate (single light-flavour) squarks. In mSUGRA/CMSSM models with tan β = 30, A 0 = −2m 0 and μ > 0, squarks and gluinos of equal mass are excluded for masses below 1700 GeV. Additional limits are set for non-universal Higgs mass models with gaugino mediation and for simplified models involving the pair production of gluinos, each decaying to a top squark and a top quark, with the top squark decaying to a charm quark and a neutralino. These limits extend the region of supersymmetric parameter space excluded by previous searches with the ATLAS detector

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV

Search for dark matter in events with heavy quarks and missing transverse momentum in pp collisions with the ATLAS detector

This article reports on a search for dark matterpair production in association with bottom or top quarks in20.3fb−1ofppcollisions collected at√s=8TeVbytheATLAS detector at the LHC. Events with large missing trans-verse momentum are selected when produced in associationwith high-momentum jets of which one or more are identifiedas jets containingb-quarks. Final states with top quarks areselected by requiring a high jet multiplicity and in some casesa single lepton. The data are found to be consistent with theStandard Model expectations and limits are set on the massscale of effective field theories that describe scalar and tensorinteractions between dark matter and Standard Model par-ticles. Limits on the dark-matter–nucleon cross-section forspin-independent and spin-dependent interactions are alsoprovided. These limits are particularly strong for low-massdark matter. Using a simplified model, constraints are set onthe mass of dark matter and of a coloured mediator suitableto explain a possible signal of annihilating dark matter