6,936 research outputs found
Converging organoids and extracellular matrix::New insights into liver cancer biology
Primary liver cancer, consisting primarily of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a heterogeneous malignancy with a dismal prognosis, resulting in the third leading cause of cancer mortality worldwide [1, 2]. It is characterized by unique histological features, late-stage diagnosis, a highly variable mutational landscape, and high levels of heterogeneity in biology and etiology [3-5]. Treatment options are limited, with surgical intervention the main curative option, although not available for the majority of patients which are diagnosed in an advanced stage. Major contributing factors to the complexity and limited treatment options are the interactions between primary tumor cells, non-neoplastic stromal and immune cells, and the extracellular matrix (ECM). ECM dysregulation plays a prominent role in multiple facets of liver cancer, including initiation and progression [6, 7]. HCC often develops in already damaged environments containing large areas of inflammation and fibrosis, while CCA is commonly characterized by significant desmoplasia, extensive formation of connective tissue surrounding the tumor [8, 9]. Thus, to gain a better understanding of liver cancer biology, sophisticated in vitro tumor models need to incorporate comprehensively the various aspects that together dictate liver cancer progression. Therefore, the aim of this thesis is to create in vitro liver cancer models through organoid technology approaches, allowing for novel insights into liver cancer biology and, in turn, providing potential avenues for therapeutic testing. To model primary epithelial liver cancer cells, organoid technology is employed in part I. To study and characterize the role of ECM in liver cancer, decellularization of tumor tissue, adjacent liver tissue, and distant metastatic organs (i.e. lung and lymph node) is described, characterized, and combined with organoid technology to create improved tissue engineered models for liver cancer in part II of this thesis. Chapter 1 provides a brief introduction into the concepts of liver cancer, cellular heterogeneity, decellularization and organoid technology. It also explains the rationale behind the work presented in this thesis. In-depth analysis of organoid technology and contrasting it to different in vitro cell culture systems employed for liver cancer modeling is done in chapter 2. Reliable establishment of liver cancer organoids is crucial for advancing translational applications of organoids, such as personalized medicine. Therefore, as described in chapter 3, a multi-center analysis was performed on establishment of liver cancer organoids. This revealed a global establishment efficiency rate of 28.2% (19.3% for hepatocellular carcinoma organoids (HCCO) and 36% for cholangiocarcinoma organoids (CCAO)). Additionally, potential solutions and future perspectives for increasing establishment are provided. Liver cancer organoids consist of solely primary epithelial tumor cells. To engineer an in vitro tumor model with the possibility of immunotherapy testing, CCAO were combined with immune cells in chapter 4. Co-culture of CCAO with peripheral blood mononuclear cells and/or allogenic T cells revealed an effective anti-tumor immune response, with distinct interpatient heterogeneity. These cytotoxic effects were mediated by cell-cell contact and release of soluble factors, albeit indirect killing through soluble factors was only observed in one organoid line. Thus, this model provided a first step towards developing immunotherapy for CCA on an individual patient level. Personalized medicine success is dependent on an organoids ability to recapitulate patient tissue faithfully. Therefore, in chapter 5 a novel organoid system was created in which branching morphogenesis was induced in cholangiocyte and CCA organoids. Branching cholangiocyte organoids self-organized into tubular structures, with high similarity to primary cholangiocytes, based on single-cell sequencing and functionality. Similarly, branching CCAO obtain a different morphology in vitro more similar to primary tumors. Moreover, these branching CCAO have a higher correlation to the transcriptomic profile of patient-paired tumor tissue and an increased drug resistance to gemcitabine and cisplatin, the standard chemotherapy regimen for CCA patients in the clinic. As discussed, CCAO represent the epithelial compartment of CCA. Proliferation, invasion, and metastasis of epithelial tumor cells is highly influenced by the interaction with their cellular and extracellular environment. The remodeling of various properties of the extracellular matrix (ECM), including stiffness, composition, alignment, and integrity, influences tumor progression. In chapter 6 the alterations of the ECM in solid tumors and the translational impact of our increased understanding of these alterations is discussed. The success of ECM-related cancer therapy development requires an intimate understanding of the malignancy-induced changes to the ECM. This principle was applied to liver cancer in chapter 7, whereby through a integrative molecular and mechanical approach the dysregulation of liver cancer ECM was characterized. An optimized agitation-based decellularization protocol was established for primary liver cancer (HCC and CCA) and paired adjacent tissue (HCC-ADJ and CCA-ADJ). Novel malignancy-related ECM protein signatures were found, which were previously overlooked in liver cancer transcriptomic data. Additionally, the mechanical characteristics were probed, which revealed divergent macro- and micro-scale mechanical properties and a higher alignment of collagen in CCA. This study provided a better understanding of ECM alterations during liver cancer as well as a potential scaffold for culture of organoids. This was applied to CCA in chapter 8 by combining decellularized CCA tumor ECM and tumor-free liver ECM with CCAO to study cell-matrix interactions. Culture of CCAO in tumor ECM resulted in a transcriptome closely resembling in vivo patient tumor tissue, and was accompanied by an increase in chemo resistance. In tumor-free liver ECM, devoid of desmoplasia, CCAO initiated a desmoplastic reaction through increased collagen production. If desmoplasia was already present, distinct ECM proteins were produced by the organoids. These were tumor-related proteins associated with poor patient survival. To extend this method of studying cell-matrix interactions to a metastatic setting, lung and lymph node tissue was decellularized and recellularized with CCAO in chapter 9, as these are common locations of metastasis in CCA. Decellularization resulted in removal of cells while preserving ECM structure and protein composition, linked to tissue-specific functioning hallmarks. Recellularization revealed that lung and lymph node ECM induced different gene expression profiles in the organoids, related to cancer stem cell phenotype, cell-ECM integrin binding, and epithelial-to-mesenchymal transition. Furthermore, the metabolic activity of CCAO in lung and lymph node was significantly influenced by the metastatic location, the original characteristics of the patient tumor, and the donor of the target organ. The previously described in vitro tumor models utilized decellularized scaffolds with native structure. Decellularized ECM can also be used for creation of tissue-specific hydrogels through digestion and gelation procedures. These hydrogels were created from both porcine and human livers in chapter 10. The liver ECM-based hydrogels were used to initiate and culture healthy cholangiocyte organoids, which maintained cholangiocyte marker expression, thus providing an alternative for initiation of organoids in BME. Building upon this, in chapter 11 human liver ECM-based extracts were used in combination with a one-step microfluidic encapsulation method to produce size standardized CCAO. The established system can facilitate the reduction of size variability conventionally seen in organoid culture by providing uniform scaffolding. Encapsulated CCAO retained their stem cell phenotype and were amendable to drug screening, showing the feasibility of scalable production of CCAO for throughput drug screening approaches. Lastly, Chapter 12 provides a global discussion and future outlook on tumor tissue engineering strategies for liver cancer, using organoid technology and decellularization. Combining multiple aspects of liver cancer, both cellular and extracellular, with tissue engineering strategies provides advanced tumor models that can delineate fundamental mechanistic insights as well as provide a platform for drug screening approaches.<br/
UMSL Bulletin 2023-2024
The 2023-2024 Bulletin and Course Catalog for the University of Missouri St. Louis.https://irl.umsl.edu/bulletin/1088/thumbnail.jp
The AddACO: A bio-inspired modified version of the ant colony optimization algorithm to solve travel salesman problems
The Travel Salesman Problem (TSP) consists in finding the minimal-length closed tour that connects the entire group of nodes of a given graph. We propose to solve such a combinatorial optimization problem with the AddACO algorithm: it is a version of the Ant Colony Optimization method that is characterized by a modified probabilistic law at the basis of the exploratory movement of the artificial insects. In particular, the ant decisional rule is here set to amount in a linear convex combination of competing behavioral stimuli and has therefore an additive form (hence the name of our algorithm), rather than the canonical multiplicative one. The AddACO intends to address two conceptual shortcomings that characterize classical ACO methods: (i) the population of artificial insects is in principle allowed to simultaneously minimize/maximize all migratory guidance cues (which is in implausible from a biological/ecological point of view) and (ii) a given edge of the graph has a null probability to be explored if at least one of the movement trait is therein equal to zero, i.e., regardless the intensity of the others (this in principle reduces the exploratory potential of the ant colony). Three possible variants of our method are then specified: the AddACO-V1, which includes pheromone trail and visibility as insect decisional variables, and the AddACO-V2 and the AddACO-V3, which in turn add random effects and inertia, respectively, to the two classical migratory stimuli. The three versions of our algorithm are tested on benchmark middle-scale TPS instances, in order to assess their performance and to find their optimal parameter setting. The best performing variant is finally applied to large-scale TSPs, compared to the naive Ant-Cycle Ant System, proposed by Dorigo and colleagues, and evaluated in terms of quality of the solutions, computational time, and convergence speed. The aim is in fact to show that the proposed transition probability, as long as its conceptual advantages, is competitive from a performance perspective, i.e., if it does not reduce the exploratory capacity of the ant population w.r.t. the canonical one (at least in the case of selected TSPs). A theoretical study of the asymptotic behavior of the AddACO is given in the appendix of the work, whose conclusive section contains some hints for further improvements of our algorithm, also in the perspective of its application to other optimization problems
Grain boundaries in polycrystalline materials for energy applications : First principles modeling and electron microscopy
Polycrystalline materials are ubiquitous in technology, and grain boundaries have long been known to affect materials properties and performance. First principles materials modeling and electron microscopy methods are powerful and highly complementary for investigating the atomic scale structure and properties of grain boundaries. In this review, we provide an introduction to key concepts and approaches for investigating grain boundaries using these methods. We also provide a number of case studies providing examples of their application to understand the impact of grain boundaries for a range of energy materials. Most of the materials presented are of interest for photovoltaic and photoelectrochemical applications and so we include a more in depth discussion of how modeling and electron microscopy can be employed to understand the impact of grain boundaries on the behavior of photoexcited electrons and holes (including carrier transport and recombination). However, we also include discussion of materials relevant to rechargeable batteries as another important class of materials for energy applications. We conclude the review with a discussion of outstanding challenges in the field and the exciting prospects for progress in the coming years
Fairness-aware Machine Learning in Educational Data Mining
Fairness is an essential requirement of every educational system, which is reflected in a variety of educational activities. With the extensive use of Artificial Intelligence (AI) and Machine Learning (ML) techniques in education, researchers and educators can analyze educational (big) data and propose new (technical) methods in order to support teachers, students, or administrators of (online) learning systems in the organization of teaching and learning. Educational data mining (EDM) is the result of the application and development of data mining (DM), and ML techniques to deal with educational problems, such as student performance prediction and student grouping. However, ML-based decisions in education can be based on protected attributes, such as race or gender, leading to discrimination of individual students or subgroups of students. Therefore, ensuring fairness in ML models also contributes to equity in educational systems. On the other hand, bias can also appear in the data obtained from learning environments. Hence, bias-aware exploratory educational data analysis is important to support unbiased decision-making in EDM.
In this thesis, we address the aforementioned issues and propose methods that mitigate discriminatory outcomes of ML algorithms in EDM tasks. Specifically, we make the following contributions:
We perform bias-aware exploratory analysis of educational datasets using Bayesian networks to identify the relationships among attributes in order to understand bias in the datasets. We focus the exploratory data analysis on features having a direct or indirect relationship with the protected attributes w.r.t. prediction outcomes.
We perform a comprehensive evaluation of the sufficiency of various group fairness measures in predictive models for student performance prediction problems. A variety of experiments on various educational datasets with different fairness measures are performed to provide users with a broad view of unfairness from diverse aspects.
We deal with the student grouping problem in collaborative learning. We introduce the fair-capacitated clustering problem that takes into account cluster fairness and cluster cardinalities. We propose two approaches, namely hierarchical clustering and partitioning-based clustering, to obtain fair-capacitated clustering.
We introduce the multi-fair capacitated (MFC) students-topics grouping problem that satisfies students' preferences while ensuring balanced group cardinalities and maximizing the diversity of members regarding the protected attribute. We propose three approaches: a greedy heuristic approach, a knapsack-based approach using vanilla maximal 0-1 knapsack formulation, and an MFC knapsack approach based on group fairness knapsack formulation.
In short, the findings described in this thesis demonstrate the importance of fairness-aware ML in educational settings. We show that bias-aware data analysis, fairness measures, and fairness-aware ML models are essential aspects to ensure fairness in EDM and the educational environment.Ministry of Science and Culture of Lower Saxony/LernMINT/51410078/E
Dynamics and Modelling of the 2015 Calbuco eruption Volcanic Debris Flows (Chile). From field evidence to a primary lahar model
The Calbuco volcanic eruption of 2015, was characterized by two explosive phases with partialand major column collapses that triggered lahars in many of the flanks of the volcano. Large lahar flows descended to the southern flank where highly fractured ice bodies were emplaced on steep slopes.In this study, we present a chronology of the volcanic flows based on a multi parameterdata set that includes social media, reports of authoritative institutions, instrumental monitoringdata and published research literature on the eruption. Our review established thatlahars in the Amarillo river began during the first phase of the eruption due to the sustained emplacement of pyroclastic flows in its catchment. In contrast, we propose that the lahars in theBlanco – Correntoso river system and the Este river were likely to have been triggered by asudden mechanical collapse of the glacier that triggered mixed avalanches which transitionedinto lahars downstream.Our observations include inundation cross-sections, estimates of flow speeds, and characterization of the morphology, grain sizes, and componentry of deposits.Field measurements are used together with instrumental data for calibrating a dynamic, physics-based model of lahar, Laharflow. We model flows in the Blanco – Correntoso river system and explore the influence of the model parameters on flow predictions in an ensemble of simulations. We develop a calibration that accounts for the substantial epistemic uncertainties in our observations and the model formulation, that seeks to determine plausible ranges for the model parameters, including those representing the lahar source. Our approach highlights the parameters in the model that have a dominant effect on the ability of the model to match observations, indicating where further development and additional observations could improve model predictions. The simulations in our ensemble that provide plausible matches to the observations are combined to produce flow inundation maps
LIPIcs, Volume 251, ITCS 2023, Complete Volume
LIPIcs, Volume 251, ITCS 2023, Complete Volum
Smart Gas Sensors: Materials, Technologies, Practical ‎Applications, and Use of Machine Learning – A Review
The electronic nose, popularly known as the E-nose, that combines gas sensor arrays (GSAs) with machine learning has gained a strong foothold in gas sensing technology. The E-nose designed to mimic the human olfactory system, is used for the detection and identification of various volatile compounds. The GSAs develop a unique signal fingerprint for each volatile compound to enable pattern recognition using machine learning algorithms. The inexpensive, portable and non-invasive characteristics of the E-nose system have rendered it indispensable within the gas-sensing arena. As a result, E-noses have been widely employed in several applications in the areas of the food industry, health management, disease diagnosis, water and air quality control, and toxic gas leakage detection. This paper reviews the various sensor fabrication technologies of GSAs and highlights the main operational framework of the E-nose system. The paper details vital signal pre-processing techniques of feature extraction, feature selection, in addition to machine learning algorithms such as SVM, kNN, ANN, and Random Forests for determining the type of gas and estimating its concentration in a competitive environment. The paper further explores the potential applications of E-noses for diagnosing diseases, monitoring air quality, assessing the quality of food samples and estimating concentrations of volatile organic compounds (VOCs) in air and in food samples. The review concludes with some challenges faced by E-nose, alternative ways to tackle them and proposes some recommendations as potential future work for further development and design enhancement of E-noses
Two-Dimensional-Based Hybrid Shape Optimisation of a 5-Element Formula 1 Race Car Front Wing under FIA Regulations
Front wings are a key element in the aerodynamic performance of Formula 1 race cars. Thus, their optimisation makes an important contribution to the performance of cars in races. However, their design is constrained by regulation, which makes it more difficult to find good designs. The present work develops a hybrid shape optimisation approach to obtain an optimal five-element airfoil front wing under the FIA regulations and 17 design parameters. A first baseline design is obtained by parametric optimisation, on which the adjoint method is applied for shape optimisation via Mesh Morphing with Radial Basis Functions. The optimal front wing candidate obtained outperforms the parametric baseline up to a 25% at certain local positions. This shows that the proposed and tested hybrid approach can be a very efficient alternative. Although a direct 3D optimisation approach could be developed, the computational costs would be dramatically increased (possibly unaffordable for such a complex five-element front wing realistic shape with 17 design parameters and regulatory constraints). Thus, the present approach is of strong interest if the computational budget is low and/or a fast new front wing design is desired, which is a frequent scenario in Formula 1 race car design.The authors want to acknowledge the financial support from the Ramón y Cajal 2021 Excellence Research Grant action from the Spanish Ministry of Science and Innovation (FSE/AGENCIA ESTATAL DE INVESTIGACIÓN), the UMA18-FEDERJA-184 grant, and the Andalusian Research, Development and Innovation Plan (PAIDI—Junta de Andalucia) fundings. Partial funding for open access charge: Universidad de Málag
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