4,073 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/
Precision Surface Processing and Software Modelling Using Shear-Thickening Polishing Slurries
Mid-spatial frequency surface error is a known manufacturing defect for aspherical and freeform precision surfaces. These surface ripples decrease imaging contrast and system signal-to-noise ratio. Existing sub-aperture polishing techniques are limited in their abilities to smooth mid-spatial frequency errors. Shear-thickening slurries have been hypothesised to reduce mid-spatial frequency errors on precision optical surfaces by increasing the viscosity at the tool-part interface. Currently, controlling the generation and mitigating existing mid-spatial frequency surface errors for aspherical and freeform surfaces requires extensive setup and the experience of seasoned workers. This thesis reports on the experimental trials of shear-thickening polishing slurries on glass surfaces. By incorporating shear-thickening slurries with the precessed bonnet technology, the aim is to enhance the ability of the precessions technology in mitigating mid-spatial frequency errors. The findings could facilitate a more streamlined manufacturing chain for precision optics for the versatile precessions technology from form correction and texture improvement, to MSF mitigation, without needing to rely on other polishing technologies. Such improvement on the existing bonnet polishing would provide a vital steppingstone towards building a fully autonomous manufacturing cell in a market of continual economic growth. The experiments in this thesis analysed the capabilities of two shear-thickening slurry systems: (1) polyethylene glycol with silica nanoparticle suspension, and (2) water and cornstarch suspension. Both slurry systems demonstrated the ability at mitigating existing surface ripples. Looking at power spectral density graphs, polyethylene glycol slurries reduced the power of the mid-spatial frequencies by ~50% and cornstarch suspension slurries by 60-90%. Experiments of a novel polishing approach are also reported in this thesis to rotate a precessed bonnet at a predetermined working distance above the workpiece surface. The rapidly rotating tool draws in the shear-thickening slurry through the gap to stiffen the fluid for polishing. This technique demonstrated material removal capabilities using cornstarch suspension slurries at a working distance of 1.0-1.5mm. The volumetric removal rate from this process is ~5% of that of contact bonnet polishing, so this aligns more as a finishing process. This polishing technique was given the term rheological bonnet finishing. The rheological properties of cornstarch suspension slurries were tested using a rheometer and modelled through CFD simulation. Using the empirical rheological data, polishing simulations of the rheological bonnet finishing process were modelled in Ansys to analyse the effects of various input parameters such as working distance, tool headspeed, precess angle, and slurry viscosity
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
Applying unsupervised learning to resolve evolutionary histories and explore the galaxy-halo connection in IllustrisTNG
We examine the effectiveness of identifying distinct evolutionary histories in IllustrisTNG-100 galaxies using unsupervised machine learning with Gaussian Mixture Models. We focus on how clustering compressed metallicity histories and star formation histories produces subpopulations of galaxies with distinct evolutionary properties (for both halo mass assembly and merger histories). By contrast, clustering with photometric colours fail to resolve such histories. We identify several populations of interest that reflect a variety of evolutionary scenarios supported by the literature. Notably, we identify a population of galaxies inhabiting the upper-red sequence, M* > 1010M⊙ that has a significantly higher ex-situ merger mass fraction present at fixed masses, and a star formation history that has yet to fully quench, in contrast to an overlapping, satellite-dominated population along the red sequence, which is distinctly quiescent. Extending the clustering to study four clusters instead of three further divides quiescent galaxies, while star forming ones are mostly contained in a single cluster, demonstrating a variety of supported pathways to quenching. In addition to these populations, we identify a handful of populations from our other clusters that are readily applicable to observational surveys, including a population related to post starburst (PSB) galaxies, allowing for possible extensions of this work in an observational context, and to corroborate results within the IllustrisTNG ecosystem.PostprintPeer reviewe
UMSL Bulletin 2022-2023
The 2022-2023 Bulletin and Course Catalog for the University of Missouri St. Louis.https://irl.umsl.edu/bulletin/1087/thumbnail.jp
Mapping the Focal Points of WordPress: A Software and Critical Code Analysis
Programming languages or code can be examined through numerous analytical lenses. This project is a critical analysis of WordPress, a prevalent web content management system, applying four modes of inquiry. The project draws on theoretical perspectives and areas of study in media, software, platforms, code, language, and power structures. The applied research is based on Critical Code Studies, an interdisciplinary field of study that holds the potential as a theoretical lens and methodological toolkit to understand computational code beyond its function. The project begins with a critical code analysis of WordPress, examining its origins and source code and mapping selected vulnerabilities. An examination of the influence of digital and computational thinking follows this. The work also explores the intersection of code patching and vulnerability management and how code shapes our sense of control, trust, and empathy, ultimately arguing that a rhetorical-cultural lens can be used to better understand code\u27s controlling influence. Recurring themes throughout these analyses and observations are the connections to power and vulnerability in WordPress\u27 code and how cultural, processual, rhetorical, and ethical implications can be expressed through its code, creating a particular worldview. Code\u27s emergent properties help illustrate how human values and practices (e.g., empathy, aesthetics, language, and trust) become encoded in software design and how people perceive the software through its worldview. These connected analyses reveal cultural, processual, and vulnerability focal points and the influence these entanglements have concerning WordPress as code, software, and platform. WordPress is a complex sociotechnical platform worthy of further study, as is the interdisciplinary merging of theoretical perspectives and disciplines to critically examine code. Ultimately, this project helps further enrich the field by introducing focal points in code, examining sociocultural phenomena within the code, and offering techniques to apply critical code methods
La traduzione specializzata all’opera per una piccola impresa in espansione: la mia esperienza di internazionalizzazione in cinese di Bioretics© S.r.l.
Global markets are currently immersed in two all-encompassing and unstoppable processes: internationalization and globalization. While the former pushes companies to look beyond the borders of their country of origin to forge relationships with foreign trading partners, the latter fosters the standardization in all countries, by reducing spatiotemporal distances and breaking down geographical, political, economic and socio-cultural barriers. In recent decades, another domain has appeared to propel these unifying drives: Artificial Intelligence, together with its high technologies aiming to implement human cognitive abilities in machinery. The “Language Toolkit – Le lingue straniere al servizio dell’internazionalizzazione dell’impresa” project, promoted by the Department of Interpreting and Translation (Forlì Campus) in collaboration with the Romagna Chamber of Commerce (Forlì-Cesena and Rimini), seeks to help Italian SMEs make their way into the global market. It is precisely within this project that this dissertation has been conceived. Indeed, its purpose is to present the translation and localization project from English into Chinese of a series of texts produced by Bioretics© S.r.l.: an investor deck, the company website and part of the installation and use manual of the Aliquis© framework software, its flagship product. This dissertation is structured as follows: Chapter 1 presents the project and the company in detail; Chapter 2 outlines the internationalization and globalization processes and the Artificial Intelligence market both in Italy and in China; Chapter 3 provides the theoretical foundations for every aspect related to Specialized Translation, including website localization; Chapter 4 describes the resources and tools used to perform the translations; Chapter 5 proposes an analysis of the source texts; Chapter 6 is a commentary on translation strategies and choices
NEMISA Digital Skills Conference (Colloquium) 2023
The purpose of the colloquium and events centred around the central role that data plays
today as a desirable commodity that must become an important part of massifying digital
skilling efforts. Governments amass even more critical data that, if leveraged, could
change the way public services are delivered, and even change the social and economic
fortunes of any country. Therefore, smart governments and organisations increasingly
require data skills to gain insights and foresight, to secure themselves, and for improved
decision making and efficiency. However, data skills are scarce, and even more
challenging is the inconsistency of the associated training programs with most curated for
the Science, Technology, Engineering, and Mathematics (STEM) disciplines.
Nonetheless, the interdisciplinary yet agnostic nature of data means that there is
opportunity to expand data skills into the non-STEM disciplines as well.College of Engineering, Science and Technolog
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