181 research outputs found
Immune contexture monitoring in solid tumors focusing on Head and Neck Cancer
Forti evidenze dimostrano una stretta interazione tra il sistema immunitario e lo sviluppo biologico e la progressione clinica dei tumori solidi. L'effetto che il microambiente immunitario del tumore può avere sul comportamento clinico della malattia è indicato come "immunecontexture". Nonostante ciò, l'attuale gestione clinica dei pazienti affetti da cancro non tiene conto di alcuna caratteristica immunologica né per la stadiazione né per le scelte terapeutiche. Il tumore della testa e del collo (HNSCC) rappresenta il 7° tumore più comune al mondo ed è caratterizzato da una prognosi relativamente sfavorevole e dall'effetto negativo dei trattamenti sulla qualità della vita dei pazienti. Oltre alla chirurgia e alla radioterapia, sono disponibili pochi trattamenti sistemici, rappresentati principalmente dalla chemioterapia a base di platino-derivati o dal cetuximab. L'immunoterapia è una nuova strategia terapeutica ancora limitata al setting palliativo (malattia ricorrente non resecabile o metastatica). La ricerca di nuovi biomarcatori o possibili nuovi meccanismi target è molto rilevante quindi nel contesto clinico dell'HNSCC. In questa tesi ci si concentrerà sullo studio di tre possibili popolazioni immunitarie pro-tumorali studiate nell'HNSCC: i neutrofili tumore-associati (TAN), le cellule B intratumorali con fenotipo immunosoppressivo e i T-reg CD8+. Particolare attenzione è data all'applicazione di moderne tecniche biostatistiche e bioinformatiche per riassumere informazioni complesse derivate da variabili cliniche e immunologiche multiparametriche e per validare risultati derivati ​​in situ, attraverso dati di espressione genica derivati da dataset pubblici. Infine, la seconda parte della tesi prenderà in considerazione progetti di ricerca clinica rilevanti, volti a migliorare l'oncologia di precisione nell'HNSCC, sviluppando modelli predittivi di sopravvivenza, confrontando procedure oncologiche alternative, validando nuovi classificatori o testando l'uso di nuovi protocolli clinici come l'uso dell'immunonutrizione.Strong evidences demonstrate a close interplay between the immune system and the biological development and clinical progression of solid tumors. The effect that the tumor immune microenvironment can have on the clinical behavior of the disease is referred as the immuno contexture. Nevertheless, the current clinical management of patients affected by cancer does not take into account any immunological features either for the staging or for the treatment choices. Head and Neck Cancer (HNSCC) represents the 7th most common cancer worldwide and it is characterized by a relatively poor prognosis and detrimental effect of treatments on the quality of life of patients. Beyond surgery and radiotherapy, few systemic treatments are available, mainly represented by platinum-based chemotherapy or cetuximab. Immunotherapy is a new therapeutical strategy still limited to the palliative setting (recurrent not resectable or metastatic disease). The search for new biomarkers or possible new targetable mechanisms is meaningful especially in the clinical setting of HNSCC. In this thesis a focus will be given on the study of three possible pro-tumoral immune populations studied in HNSCC: the tumor associated neutrophils (TAN), intratumoral B-cells with a immunosuppressive phenotype and the CD8+ T-regs. Biostatistical and bioinformatical techniques are applied to summarize complex information derived from multiparametric clinical and immunological variables and to validate in-situ derived findings through gene expression data of public available datasets. Lastly, the second part of the thesis will take into account relevant clinical research projects, aimed at improving the precision oncology in HNSCC developing survival prediction models, comparing alternative oncological procedures, validating new classifiers or testing the use of novel clinical protocols as the use of immunnutrition
Stability and bifurcation analysis of a multi-delay model for mosaic disease transmission
A mathematical model is developed for analysis of the spread of mosaic disease in plants, which account for incubation period and latency that are represented by time delays. Feasibility and stability of different equilibria are studied analytically and numerically. Conditions that determine the type of behavior exhibited by the system are found in terms of various parameters. We have derived the basic reproduction number and identify the conditions resulting in eradication of the disease, as well as those that lead to the emergence of stable oscillations in the population of infected plants, as a result of Hopf bifurcation of the endemic equilibrium. Numerical simulations are performed to verify the analytical results and also to illustrate different dynamical regimes that can be observed in the system. In this research, the stabilizing role of both the time delay has been established i.e. when delay time is large, disease will persist if the infection rate is higher. The results obtained here are useful for plant disease management
Cosmology from random entanglement
We construct entangled microstates of a pair of holographic CFTs whose dual
semiclassical description includes big bang-big crunch AdS cosmologies in
spaces without boundaries. The cosmology is supported by inhomogeneous heavy
matter and it partially purifies the bulk entanglement of two disconnected
auxiliary AdS spacetimes. We show that the island formula for the fine grained
entropy of one of the CFTs follows from a standard gravitational replica trick
calculation. In generic settings, the cosmology is contained in the
entanglement wedge of one of the two CFTs. We then investigate properties of
the cosmology-to-boundary encoding map, and in particular, its non-isometric
character. Restricting our attention to a specific class of states on the
cosmology, we provide an explicit, and state-dependent, boundary representation
of operators acting on the cosmology. Finally, under genericity assumptions, we
argue for a non-isometric to approximately-isometric transition of the
cosmology-to-boundary map for ``simple'' states on the cosmology as a function
of the bulk entanglement, with tensor network toy models of our setup as a
guide.Comment: 62 pages, 22 figures + appendices. v2: minor corrections, updated
references and Fig. 1
Energy Stable and Structure-Preserving Schemes for the Stochastic Galerkin Shallow Water Equations
The shallow water flow model is widely used to describe water flows in
rivers, lakes, and coastal areas. Accounting for uncertainty in the
corresponding transport-dominated nonlinear PDE models presents theoretical and
numerical challenges that motivate the central advances of this paper. Starting
with a spatially one-dimensional hyperbolicity-preserving,
positivity-preserving stochastic Galerkin formulation of the
parametric/uncertain shallow water equations, we derive an entropy-entropy flux
pair for the system. We exploit this entropy-entropy flux pair to construct
structure-preserving second-order energy conservative, and first- and
second-order energy stable finite volume schemes for the stochastic Galerkin
shallow water system. The performance of the methods is illustrated on several
numerical experiments
HGF/c-Met Pathway Inhibition Combined with Chemotherapy Increases Cytotoxic T-cell infiltration and Inhibits Pancreatic Tumour Growth and Metastasis
Pancreatic cancer (PC) is characterised by desmoplasia and immunosuppression, factors in which pancreatic stellate cells (PSCs) play a key role. PSCs also interact with cancer cells to facilitate cancer progression. The hepatocyte growth factor (HGF)/c-MET pathway is a key mediator of this interaction. This thesis aimed to assess the effects of inhibiting this pathway (with and without chemotherapy) on tumour growth, tumour metastasis, T-cell infiltration, and the gut microbiome, using immunocompetent transgenic and syngeneic (orthotopic) models of PC and elucidating the mechanisms mediating the above effects using in vitro 2D and 3D cultures.
The study has yielded novel findings as follows:
Compared to untreated mice and treatments with single or dual combinations of HGF inhibitor (Hi), c-MET inhibitor (Ci), and gemcitabine: i) In transgenic KPC mice, HGF inhibition + c-MET inhibition + gemcitabine (triple therapy) significantly decreased precursor PanIN lesion density, reduced stemness and significantly increased total (CD3+) and cytotoxic (CD8+) T-cell infiltration, while decreasing helper T-cells (CD4). ii) In the orthotopic model, triple therapy resulted in a) the most significant reduction in tumour volume, b) increased total T-cell and cytotoxic T-cell infiltration, c) decreased epithelial-mesenchymal transition, and d) elimination of visible metastasis. Regarding the gut microbiome, compared to healthy (non-tumour-bearing mice), untreated tumour-bearing mice exhibited decreased alpha diversity, an abundance of pathogenic bacteria, and abnormal beta diversity. Hi+Ci and triple therapy significantly improved alpha diversity associated with a decrease in pathogenic bacteria. Interestingly, beta diversity analysis demonstrated that only the triple treated mouse microbiome clustered closely with healthy mice, suggesting the normalisation of gut microbiota in the former group.
2D in vitro studies showed that the effects of triple therapy on tumour volume and metastasis were mediated by inhibition of pancreatic stellate cell-induced KPC (mouse cancer cell line) proliferation, migration, and cytokine (TGFβ and IL6) secretion. 3D studies showed that only triple therapy could disintegrate established spheroids.
In conclusion, inhibition of both the ligand and receptor of the HGF/c-MET pathway combined with chemotherapy successfully inhibited pancreatic cancer progression and normalised the gut microbiome. These findings provide a strong platform for translating the triple therapy approach into clinical trials for PC
Reconstruction of Quantum Particle Statistics: Bosons, Fermions, and Transtatistics
Identical quantum particles exhibit only two types of statistics: bosonic and
fermionic. Theoretically, this restriction is commonly established through the
symmetrization postulate or (anti)commutation constraints imposed on the
algebra of creation and annihilation operators. The physical motivation for
these axioms remains poorly understood, leading to various generalizations by
modifying the mathematical formalism in somewhat arbitrary ways. In this work,
we take an opposing route and classify quantum particle statistics based on
operationally well-motivated assumptions. Specifically, we consider that a) the
standard (complex) unitary dynamics defines the set of single-particle
transformations, and b) phase transformations act locally in the space of
multi-particle systems. We develop a complete characterization, which includes
bosons and fermions as basic statistics with minimal symmetry. Interestingly,
we have discovered whole families of novel statistics (dubbed transtatistics)
accompanied by hidden symmetries, generic degeneracy of ground states, and
spontaneous symmetry breaking -- effects that are (typically) absent in
ordinary statistics.Comment: 16 pages, 4 figur
New Aspects of Scattering Amplitudes, Higher-k Amplitudes, and Holographic Quark Gluon Plasmas
We present new results on different aspects of quantum field theory, which are divided into three main parts. In part I, we find and prove a new behavior of massless tree-level scattering amplitudes, including the biadjoint scalar theory, the U(N) non-linear sigma model, and the special Galileon, within specific subspaces of the kinematic space. We also derive new formulas for the double-ordered biadjoint scalar and amplitudes, which can be obtained as integrals over the positive tropical Grassmannian and under limiting procedures on the kinematic invariants. This reveals surprising connections with cubic amplitudes. We also present alternative versions of the formulas for amplitudes from combinatorial considerations in terms of non-crossing chord diagrams. In part II, we investigate the generalization of quantum field theory introduced by Cachazo, Early, Guevara and Mizera (CEGM) in 2019. We use soft limits to determine the number of singular solutions of the generalized scattering equations in certain cases and propose a general classification of all configurations that can support singular solutions. We also describe the generalized Feynman diagrams that compute CEGM amplitudes. These are planar arrays of Feynman diagrams satisfying certain compatibility conditions, and we propose combinatorial bootstrap methods to obtain them. Finally, in part III, we analyze different types of quark gluon plasmas in the presence of a background magnetic field using top-down holographic models. We explore conformal and nonconformal theories as consistent truncations of gauged supergravity and identify a universal behavior in the gauge theory
Cluster algebras and tilings for the m=4 amplituhedron
The amplituhedron is the image of the positive Grassmannian
under the amplituhedron map induced by a positive linear map . It was originally introduced in physics in order to give a
geometric interpretation of scattering amplitudes. More specifically, one can
compute scattering amplitudes in SYM by decomposing the amplituhedron
into 'tiles' (closures of images of -dimensional cells of on which the amplituhedron map is injective) and summing up the 'volumes'
of the tiles. Such a decomposition into tiles is called a tiling. In this
article we deepen our understanding of tiles and tilings of the
amplituhedron. We prove the cluster adjacency conjecture for BCFW tiles of
, which says that facets of BCFW tiles are cut out by collections
of compatible cluster variables for . We also give an explicit
description of each BCFW tile as the subset of where certain
cluster variables have particular signs. And we prove the BCFW tiling
conjecture, which says that any way of iterating the BCFW recurrence gives rise
to a tiling of the amplituhedron . Along the way we construct
many explicit seeds for the comprised of high-degree cluster
variables, which may be of independent interest in the study of cluster
algebras
Methods of free probability
This is a joint introduction to classical and free probability, which are
twin sisters. We first review the foundations of classical probability, notably
with the main limiting theorems (CLT, CCLT, PLT, CPLT), and with a look into
examples coming from Lie groups and random matrices. Then we present the
foundations and main results of free probability, notably with free limiting
theorems, and with a look into examples coming from quantum groups and random
matrices. We discuss then a number of more advanced aspects, in relation on one
hand with free geometry, and on the other hand with questions in operator
algebras coming from subfactor theory.Comment: 400 pages. arXiv admin note: text overlap with arXiv:2208.0360
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