1,646 research outputs found

    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    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/

    LIPIcs, Volume 251, ITCS 2023, Complete Volume

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    LIPIcs, Volume 251, ITCS 2023, Complete Volum

    Proceedings of SIRM 2023 - The 15th European Conference on Rotordynamics

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    It was our great honor and pleasure to host the SIRM Conference after 2003 and 2011 for the third time in Darmstadt. Rotordynamics covers a huge variety of different applications and challenges which are all in the scope of this conference. The conference was opened with a keynote lecture given by Rainer Nordmann, one of the three founders of SIRM “Schwingungen in rotierenden Maschinen”. In total 53 papers passed our strict review process and were presented. This impressively shows that rotordynamics is relevant as ever. These contributions cover a very wide spectrum of session topics: fluid bearings and seals; air foil bearings; magnetic bearings; rotor blade interaction; rotor fluid interactions; unbalance and balancing; vibrations in turbomachines; vibration control; instability; electrical machines; monitoring, identification and diagnosis; advanced numerical tools and nonlinearities as well as general rotordynamics. The international character of the conference has been significantly enhanced by the Scientific Board since the 14th SIRM resulting on one hand in an expanded Scientific Committee which meanwhile consists of 31 members from 13 different European countries and on the other hand in the new name “European Conference on Rotordynamics”. This new international profile has also been emphasized by participants of the 15th SIRM coming from 17 different countries out of three continents. We experienced a vital discussion and dialogue between industry and academia at the conference where roughly one third of the papers were presented by industry and two thirds by academia being an excellent basis to follow a bidirectional transfer what we call xchange at Technical University of Darmstadt. At this point we also want to give our special thanks to the eleven industry sponsors for their great support of the conference. On behalf of the Darmstadt Local Committee I welcome you to read the papers of the 15th SIRM giving you further insight into the topics and presentations

    Advances and Applications of DSmT for Information Fusion. Collected Works, Volume 5

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    This fifth volume on Advances and Applications of DSmT for Information Fusion collects theoretical and applied contributions of researchers working in different fields of applications and in mathematics, and is available in open-access. The collected contributions of this volume have either been published or presented after disseminating the fourth volume in 2015 in international conferences, seminars, workshops and journals, or they are new. The contributions of each part of this volume are chronologically ordered. First Part of this book presents some theoretical advances on DSmT, dealing mainly with modified Proportional Conflict Redistribution Rules (PCR) of combination with degree of intersection, coarsening techniques, interval calculus for PCR thanks to set inversion via interval analysis (SIVIA), rough set classifiers, canonical decomposition of dichotomous belief functions, fast PCR fusion, fast inter-criteria analysis with PCR, and improved PCR5 and PCR6 rules preserving the (quasi-)neutrality of (quasi-)vacuous belief assignment in the fusion of sources of evidence with their Matlab codes. Because more applications of DSmT have emerged in the past years since the apparition of the fourth book of DSmT in 2015, the second part of this volume is about selected applications of DSmT mainly in building change detection, object recognition, quality of data association in tracking, perception in robotics, risk assessment for torrent protection and multi-criteria decision-making, multi-modal image fusion, coarsening techniques, recommender system, levee characterization and assessment, human heading perception, trust assessment, robotics, biometrics, failure detection, GPS systems, inter-criteria analysis, group decision, human activity recognition, storm prediction, data association for autonomous vehicles, identification of maritime vessels, fusion of support vector machines (SVM), Silx-Furtif RUST code library for information fusion including PCR rules, and network for ship classification. Finally, the third part presents interesting contributions related to belief functions in general published or presented along the years since 2015. These contributions are related with decision-making under uncertainty, belief approximations, probability transformations, new distances between belief functions, non-classical multi-criteria decision-making problems with belief functions, generalization of Bayes theorem, image processing, data association, entropy and cross-entropy measures, fuzzy evidence numbers, negator of belief mass, human activity recognition, information fusion for breast cancer therapy, imbalanced data classification, and hybrid techniques mixing deep learning with belief functions as well

    Automatic Generation of Personalized Recommendations in eCoaching

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    Denne avhandlingen omhandler eCoaching for personlig livsstilsstøtte i sanntid ved bruk av informasjons- og kommunikasjonsteknologi. Utfordringen er å designe, utvikle og teknisk evaluere en prototyp av en intelligent eCoach som automatisk genererer personlige og evidensbaserte anbefalinger til en bedre livsstil. Den utviklede løsningen er fokusert på forbedring av fysisk aktivitet. Prototypen bruker bærbare medisinske aktivitetssensorer. De innsamlede data blir semantisk representert og kunstig intelligente algoritmer genererer automatisk meningsfulle, personlige og kontekstbaserte anbefalinger for mindre stillesittende tid. Oppgaven bruker den veletablerte designvitenskapelige forskningsmetodikken for å utvikle teoretiske grunnlag og praktiske implementeringer. Samlet sett fokuserer denne forskningen på teknologisk verifisering snarere enn klinisk evaluering.publishedVersio

    Research and development for the data, trigger and control card in preparation for Hi-Lumi lhc

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    When the Large Hadron Collider (LHC) increases its luminosity by an order of magnitude in the coming decade, the experiments that sit upon it must also be upgraded to continue to their physics performance in the increasingly demanding environment. To achieve this, the Compact Muon Solenoid (CMS) experiment will make use of tracking information in the Level-1 trigger for the first time, meaning that track reconstruction must be achieved in less than 4 μs in an all-FPGA architecture. MUonE is an experiment aiming to make an accurate measurement of the the hadronic contribution to the anomalous magnetic moment of the muon. It will achieve this by making use of similar apparatus to that designed for CMS and benefit from the research and development efforts there. This thesis presents both development and testing work for the readout chain from tracker module to back-end processing card, as well as the results and analysis of a beam test used to validate this chain for both CMS and the MUonE experiment.Open Acces

    The Global Riverine Hydrokinetic Resource

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    3D Visualisation - An Application and Assessment for Computer Network Traffic Analysis

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    The intent of this research is to develop and assess the application of 3D data visualisation to the field of computer security. The growth of available data relating to computer networks necessitates a more efficient and effective way of presenting information to analysts in support of decision making and situational awareness. Advances in computer hardware and display software have made more complex and interactive presentation of data in 3D possible. While many attempts at creation of data-rich 3D displays have been made in the field of computer security, they have not become the tool of choice in the industry. There is also a limited amount of published research in the assessment of these tools in comparison to 2D graphical and tabular approaches to displaying the same data. This research was conducted through creation of a novel abstraction framework for visualisation of computer network data, the Visual Interactive Network Analysis Framework (VINAF). This framework was implemented in software and the software prototype was assessed using both a procedural approach applied to a published forensics challenge and also through a human participant based experiment. The key contributions to the fields of computer security and data visualisation made by this research include the creation of a novel abstraction framework for computer network traffic which features several new visualisation approaches. An implementation of this software was developed for the specific cybersecurity related task of computer network traffic analysis and published under an open source license to the cybersecurity community. The research contributes a novel approach to human-based experimentation developed during the COVID-19 pandemic and also implemented a novel procedure-based testing approach to the assessment of the prototype data visualisation tool. Results of the research showed, through procedural experimentation, that the abstraction framework is effective for network forensics tasks and exhibited several advantages when compared to alternate approaches. The user participation experiment indicated that most of the participants deemed the abstraction framework to be effective in several task related to computer network traffic analysis. There was not a strong indication that it would be preferred over existing approaches utilised by the participants, however, it would likely be used to augment existing methods

    Development of Bridge Information Model (BrIM) for digital twinning and management using TLS technology

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    In the current modern era of information and technology, the concept of Building Information Model (BIM), has made revolutionary changes in different aspects of engineering design, construction, and management of infrastructure assets, especially bridges. In the field of bridge engineering, Bridge Information Model (BrIM), as a specific form of BIM, includes digital twining of the physical asset associated with geometrical inspections and non-geometrical data, which has eliminated the use of traditional paper-based documentation and hand-written reports, enabling professionals and managers to operate more efficiently and effectively. However, concerns remain about the quality of the acquired inspection data and utilizing BrIM information for remedial decisions in a reliable Bridge Management System (BMS) which are still reliant on the knowledge and experience of the involved inspectors, or asset manager, and are susceptible to a certain degree of subjectivity. Therefore, this research study aims not only to introduce the valuable benefits of Terrestrial Laser Scanning (TLS) as a precise, rapid, and qualitative inspection method, but also to serve a novel sliced-based approach for bridge geometric Computer-Aided Design (CAD) model extraction using TLS-based point cloud, and to contribute to BrIM development. Moreover, this study presents a comprehensive methodology for incorporating generated BrIM in a redeveloped element-based condition assessment model while integrating a Decision Support System (DSS) to propose an innovative BMS. This methodology was further implemented in a designed software plugin and validated by a real case study on the Werrington Bridge, a cable-stayed bridge in New South Wales, Australia. The finding of this research confirms the reliability of the TLS-derived 3D model in terms of quality of acquired data and accuracy of the proposed novel slice-based method, as well as BrIM implementation, and integration of the proposed BMS into the developed BrIM. Furthermore, the results of this study showed that the proposed integrated model addresses the subjective nature of decision-making by conducting a risk assessment and utilising structured decision-making tools for priority ranking of remedial actions. The findings demonstrated acceptable agreement in utilizing the proposed BMS for priority ranking of structural elements that require more attention, as well as efficient optimisation of remedial actions to preserve bridge health and safety
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