1,721,478 research outputs found
Myeloid derived-suppressor cells as a potential target of immunotherapy in notch dependent T-cell acute lymphoblastic leukemia
No full textNotch receptors play crucial roles in T-cell development, and their dysregulation leads to the development of T-cell Acute Lymphoblastic Leukemia (T-ALL), a condition that, as of now, lacks a definitive cure. Notch3 transgenic mice (N3-tg) represent a well- established model for T-ALL, where the constitutive activation of the receptor in immature thymocytes initiates an aggressive disease characterized by the expansion of tumoral T cells in the periphery. These tumor cells can trigger a Notch/IL-6-dependent accumulation of Myeloid-Derived Suppressor Cells (MDSCs), which, in turn, support tumor progression. MDSCs are an immature cell subset that inhibits immune responses, creating a conductive environment for tumor growth. Programmed cell death 1 (PD-1) is an inhibitory receptor of immune responses, recognized for its role as a suppressor of T-cell activation and proliferation when interacting with the PD-L1 ligand. MDSCs contribute to tumor progression through various mechanisms, including the expression of PD-L1, resulting in the inhibition of PD-1 expressing cells within the tumor microenvironment, such as T- and NK-cells.
The main aim of my thesis was to identify MDSC targets and mechanisms of action in the tumor microenvironment of our Notch-dependent murine model of T-ALL, with regard to their potential role in inhibiting NK activity, possibly through the PD-1/PD-L1 axis. Thus, this research ultimately aims to develop an innovative combined therapy for T-ALL, targeting tumor T cells, enhancing NK activity, and modulating MDSC function.
My data demonstrated that in N3-tg mice, number and function of NK cells decline significantly, while the percentage of them expressing PD-1 increases, during disease progression. This coincided with an expansion of functional MDSCs and in particular of the PD-L1+ fraction. This inverse correlation suggests us that NK impairment could be driven by MDSCs. Indeed, through in vitro cytotoxicity assay based on co-culture of NK cells with MDSCs, both from spleen of N3-tg mice, we confirmed that MDSCs can significantly hinder NK cell function.
Finally, treating N3-tg mice with anti-PD-L1 blocking antibodies markedly inhibits T- ALL progression, by significantly reductions in splenomegaly and absolute count of tumor cells. Moreover, the treatment led to a substantial decrease in overall MDSC numbers, particularly within the PD-L1-expressing subset. Concurrently, there was a noticeable expansion of PD-1+ NK cells, exhibiting a significantly heightened cytotoxic activity compared to the control group.
In conclusion, my results suggest that in Notch-dependent T-ALL, MDSCs may hinder the anti-tumor activity of NK cells via the PD-1/PD-L1 axis, thus favoring disease progression. Then, molecules and cells of this network could potentially serve as prognostic markers and/or targets for innovative therapies
Eterotopic autotransplantation of the pancreas body-tail in the pig: surgical and microsurgical techniques
No full textMulti-Neighborhood Simulated Annealing for the Capacitated Dispersion Problem
Full text linkWe propose a novel Multi-Neighborhood Simulated Annealing approach to address the Capacitated Dispersion Problem. It makes use of three neighborhoods, adapted from similar proposals from the literature. Our search method, properly engineered and tuned, is able to consistently improve the state-of-the-art methods on almost all instances from public benchmarks. In addition, we highlight the limitations of the current datasets and we propose a new, more challenging one, obtained by sampling data from real maps and population density. Finally, we propose two compact mathematical models that obtain good bounds on small/medium size instances as well as, with long runs, on large ones
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Multi-constructor CMSA for the maximum disjoint dominating sets problem
Full text linkWe propose the Multi-Constructor CMSA, a Construct, Merge, Solve and Adapt (CMSA) algorithm that employs multiple heuristic procedures, respectively solution constructors, for the Maximum Disjoint Dominating Sets Problem (MDDSP). At every iteration of the search procedure, the solution components built by the constructors are merged into a sub-instance, which is subsequently solved by an exact solver and then adapted to keep only beneficial solution components. In our CMSA the solution constructors are chosen at random according to their relative probabilities, which are adapted during the search, through a mechanism based on reinforcement learning. We test two variants of the new Multi-Constructor CMSA that employ, respectively, two and six solution constructors, on a new set of 3600 problem instances, encompassing random graphs, Watts–Strogatz networks and Barabási-Albert networks, generated through a Hammersley sampling procedure on the instance space. We compare our algorithm against six heuristics from the literature, as well as with the standard version of CMSA. Furthermore, we employ an integer linear programming (ILP) model that is able to achieve a good performance for small, sparse graphs. Overall, the experimental results show that all versions of CMSA outperform by a large margin the previous state of the art and that, among the variants of CMSA, the novel version that combines two constructors provides slightly better results than the other ones, more prominently on larger graphs
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery
No full textIleus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery
electrochemical oxidation of dimers of nicotinamide adenindinucleotide in acqueous medium
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