Biochemical and Immunological Study of the Roles of GARP/TGF-β Axis in Cancer

GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGF-β1 mostly expressed on regulatory T cells (Treg) and platelets. Although GARP has been extensively studied for the ability to enhance latent TGF- β1 activation in the context of Treg, the expression and relevant functions on cancer cells and platelets had not been explored when this work started 4 years ago. In addition, a soluble form of GARP has been described as shed from the Treg cell surface; however, the mechanism to explain the soluble molecule formation and how it becomes biologically active remains elusive. The results contained in this dissertation cover several unknown aspects of GARP biology and shed light on GARP as a potential therapeutic target in cancer treatment and prognosis. The first part of the results section focuses on the mechanism behind the formation and the biological activity of soluble GARP. Here we describe two putative mechanisms that explain the generation of the soluble protein. The first mechanism is mediated by thrombin that enzymatically cleaves surface GARP to generate two cleaved products. The second mechanism is mediated by extracellular vesicles (EVs) secreted by cells, specifically exosomes, which include GARP/latent TGF-β as a complex. Importantly, this part of the thesis dissertation demonstrated the importance of integrins belonging to the alpha V family that mediate the endocytosis of soluble GARP (sGARP) in epithelial cells. In the second chapter of the results section, I report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGF-β1 in the TME. In collaboration with other members in Dr. Zihai Li’s laboratory, I found that human breast, lung, colon, and prostate cancers expressed GARP aberrantly. In genetic studies utilizing normal mammary gland epithelial and carcinoma cells, GARP expression increased TGF-β bioactivity and promoted malignant transformation in immunodeficient mice. In immunocompetent breast carcinoma– bearing mice, GARP overexpression promoted Foxp3+ Treg cell activity, which in turn contributed in enhancing cancer progression and metastasis. Notably, administration of a GARP-specific monoclonal antibody, made by Dr. Zihai Li’s laboratory, limited metastasis in an orthotopic model of human breast cancer. Overall, these results define the oncogenic effects of the GARP–TGFβ1 axis in the TME and suggest mechanisms that might be exploited for diagnostic and therapeutic purposes. These results have been summarized and published in the journal Cancer Research in a paper entitled “Expression of TGF-β Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer”1. In the third part of the result section, I focused on the role of platelet GARP. Here, I hypothesized that constitutive GARP expression on platelets enhances the activation of latent TGF-β1 released by platelets. This phenomenon is critical in the cross-talk between platelets and cancer cells where GARP promotes malignancy and resistance to therapy. Indeed, platelet-specific deletion of GARP-encoding gene Lrrc32 blunted TGF-β1 activity at the tumor site and potentiated protective immunity against both melanoma and colon cancer. This work was recently published in Science Immunology in an article entitled: “Platelets Subvert T Cell Immunity Against Cancer via GARP/TGF-β Axis”2. Overall, the results included in this thesis demonstrate that 1) the formation of soluble GARP is mediated by two novel mechanisms that can be exploited for cancer immunotherapy; 2) GARP is expressed on cancer cells and has oncogenic properties; and 3) GARP/TGF-β axis on platelets reduces the efficacy of the anti- tumor immunity by blunting anti-tumor T cell activity

Recent Advancements in Inverse Reinforcement Learning

Inverse reinforcement learning (IRL) has seen significant advancements in recent years. This class of approaches aims to efficiently learn the underlying reward function that rationalizes the behavior exhibited by expert agents, often represented by humans. In contrast to mere behavioral cloning, the reconstruction of a reward function yields appealing implications, as it allows for more effective interpretability of the expert’s decisions and provides a transferable specification of the expert’s objectives for application in even different environments. Unlike the well-understood field of reinforcement learning (RL) from a theoretical perspective, IRL still grapples with limited understanding, significantly constraining its applicability. A fundamental challenge in IRL is the inherent ambiguity in selecting a reward function, given the existence of multiple candidate functions, all explaining the expert’s behavior. In this talk, I will survey three of my papers that have made notable contributions to the IRL field: “Provably Efficient Learning of Transferable Rewards”, “Towards Theoretical Understanding of Inverse Reinforcement Learning”, and “Inverse Reinforcement Learning with Sub-optimal Experts". The central innovation introduced by the first paper is a novel formulation of the IRL problem that overcomes the issue of ambiguity. IRL is reframed as the problem of learning the feasible reward set, which is the set of all rewards that can explain the expert’s behavior. This approach postpones the selection of the reward function, thereby circumventing the ambiguity issues. Furthermore, the feasible reward set exhibits convenient geometric properties that enable the development of efficient algorithms for its computation. Building on this novel formulation of IRL, the second paper addresses the problem of efficiently learning the feasible reward set when the environment and the expert’s policy are not known in advance. It introduces a novel way to assess the dissimilarity between feasible reward sets based on the Hausdorff distance and presents a new PAC (probabilistic approximately correct) framework. The most significant contribution of this paper is the introduction of the first sample complexity lower bound, which highlights the challenges inherent in the IRL problem. Deriving this lower bound necessitated the development of novel technical tools. The paper also demonstrates that when a generative model of the environment is available, a uniform sampling strategy achieves a sample complexity that matches the lower bound, up to logarithmic factors. Finally, in the third paper, the IRL problem in the presence of sub-optimal experts is investigated. Specifically, the paper assumes the availability of multiple sub-optimal experts, in addition to the expert agent, which provides additional demonstrations, associated with a known quantification of the maximum amount of sub-optimality. The paper shows that this richer information mitigates the ambiguity problem, significantly reducing the size of the feasible reward set while retaining its favorable geometric properties. Furthermore, the paper explores the associated statistical problem and derives novel lower bounds for sample complexity, along with almost matching algorithms. These selected papers represent notable advancements in IRL, contributing to the establishment of a solid theoretical foundation for IRL and extending the framework to accommodate scenarios with sub-optimal experts

A comparison of two modalities of extensive reading with young learners of English

Treballs Finals del Grau d'Estudis Anglesos, Facultat de Filologia, Universitat de Barcelona, Curs: 2017-2018, Tutor: Elsa Tragant Mestres[eng] This paper is part of a larger project carried by the members of the GRAL research group (Grup de Recerca en Adquisició de Llengües) about maximising the role of L2 input. The present study analyses primarily the students’ perceptions towards a four-week intervention intended to compare two modalities of Extensive Reading: reading through multiple exposures and reading extensively with audio support. This paper analyses the data collected from questionnaires and interviews that students completed at the end of the intervention.[cat] Aquest treball és part d’un projecte realitzat per els membres del GRAL (Grup de Recerca en Adquisició de Llengües) sobre maximitzar el rol de l’input en una segona llengua. En aquest estudi s’analitzen les percepcions i actituds dels alumnes cap a una intervenció de quatre setmanes destinada a comparar dues modalitats de lectura extensiva: lectura amb múltiples exposicions i lectura extensiva amb suport d’àudio. Aquest treball per tant, pretén fer un anàlisis de totes les dades recollides dels qüestionaris i les entrevistes que els alumnes van completar a final de la intervenció

Lapped joints of bars in bundles

The approach of European and North American Design Code rules for design of lapped joints of reinforcing bars within a bundle differ markedly, with the former permitting the same or shorter laps with respect to laps of individual bars, while the other requires longer laps. This paper reports an experimental in- vestigation to evaluate performance of lapped joints in which individual reinforcing bars within a bundle of two or three bars are lapped. The results show that it is not necessary to increase lap lengths of individual bars within a bundle, and that failure is less brittle where lap joints confined by links are staggered longitudinally, whether the lap is between individual bars or is of one bar in a pair or bundle. The outcome does, however, question the validity of the reductions permitted in EC2 for staggering laps, and suggests that it would be prudent to suspend use of the α6 reduction factor for proportion of bars lapped at a section pending more tho- rough investigatio

Influence of the relative rib area on bond behaviour

Steel-to-concrete bond is a basic aspect of the behaviour of reinforced concrete structures both at serviceability and ultimate states. When bond rules were originally developed, experimental results were mainly obtained on normal- strength concrete and a minimum relative rib area (bond index) was required by building codes to ensure good bond properties. The arrival into the market of high-performance concrete and newer structural needs may require different bond indexes. In the present paper, the experimental results of pull-out tests on short anchorages are presented. Several pull-out tests on ribbed bars, embedded in cubes of normal- and high-strength concrete with a concrete cover of 4.5 times the bar diameter, were carried out in order to better understand the influence of the relative rib area and bar diameter on the local bond behaviour, as well as on the splitting crack width generated by the wedging action of ribs. A total of 96 tests were performed on machined bars of three different diameters (12, 16 and 20 mm) with a bond index ranging from 0.040 to 0.105. The results of 55 pull-out tests on commercial hot-rolled ribbed bars of four different diameters (12, 20, 40 and 50 mm) are also presented to confirm that the bond response also depends on bar diameter (size effect). Experimental results provide information concerning the influence of the relative rib area on bond strength and on the bursting force due to the rib’s wedge action. As the minimum measured bond strength of rebars was always markedly greater than the minimum bond strength required by building codes even when low bond indexes were adopted, the test results point out the possibility of reducing the minimum value of the relative rib area required by Eurocode 2 without limiting the safety coefficient of bond. The reduction also allows a higher structural ductility that can be achieved due to a greater strain penetration of the rebars from concrete cracks

On Bayesian new edge prediction and anomaly detection in computer networks

Monitoring computer network traffic for anomalous behaviour presents an important security challenge. Arrivals of new edges in a network graph represent connections between a client and server pair not previously observed, and in rare cases these might suggest the presence of intruders or malicious implants. We propose a Bayesian model and anomaly detection method for simultaneously characterising existing network structure and modelling likely new edge formation. The method is demonstrated on real computer network authentication data and successfully identifies some machines which are known to be compromised

Is fiscal consolidation self-defeating? A Panel-VAR analysis for the Euro area countries

This paper studies the effects of fiscal consolidation on the debt-to-GDP ratio of 11 Euro area countries. Using a quarterly fiscal Panel VAR allows us to trace out the dynamics of the debt-to-GDP ratio following a fiscal shock and to disentangle the main channels through which fiscal consolidation affects the debt ratio. We define a fiscal consolidation episode as self-defeating if the debt-to-GDP ratio does not decrease compared to the pre-shock level. Our main finding is that when consolidation is implemented via a cut in government primary spending, the debt ratio, after an initial increase, falls to below its pre-shock level. When instead the consolidation is implemented via an increase in government revenues, the initial increase in the debt ratio is stronger and, eventually, the debt ratio reverts to its pre-shock level, resulting in what we call self-defeating austerity

Experimental Results on Staggered Lapped Bars in FRC

The paper presents experimental results on lap splices in fiber reinforced concrete (FRC). Four point bending tests were carried out on several full-scale beams with all or part of the longitudinal reinforcement lap spliced at mid-span. The beams were reinforced with either 16 mm or 20 mm diameter rebars and included various lap splices configurations varying the percentage of lapped bars. The behaviour of lapped bars in FRC with a volume content of steel hooked fibres equal to 0.5% was investigated. The results show that the post-peak behaviour of FRC can enhance the strength of staggered lapped splices as well as it can reduce their brittleness, thus allowing a reduction of lap length when only a portion of bars at a section are lapped. The results show also the benefits on the durability of concrete members due to the capability of the fibres to markedly reduce the splitting cracks along the splice at service loadings