2,557 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
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
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
Image simulations of highly magnified clumpy galaxies
Strong gravitational lensing is a fundamental tool for studying the high-redshift Universe since the magnification it produces enables it to reach spatial resolutions that would otherwise be unattainable. Background sources placed in proximity to the caustics of a galaxy cluster lead to such a high degree of magnification, that they allow for the observation of regions as small as stellar clusters. This is a crucial process to comprehend the mechanisms responsible for galaxy formation and evolution in the early Universe.
In this Thesis, we develop a python-based pipeline aimed at simulating observations of high-redshift clumpy galaxies with three different instruments: HST/ACS, JWST/NIRCAM and Euclid/VIS. These sources are modeled by combining the host galaxy and stellar clumps as multiple luminous components. Each of them is defined using elliptical SĂ©rsic surface brightness profiles. We place these sources near the caustics of five different galaxy clusters in order to generate highly magnified gravitational arcs.
This tool is highly flexible, allowing us to change the parameters in order to simulate very diverse
sources under different observing conditions. Our simulator, hence, enables us to directly compare the performance of past, present, and future instruments when dealing with sub-kpc substructures.
The second part of this work shows two applications of our simulator. Firstly, we focus on the
issue of identifying stellar clumps in strongly lensed galaxies. In order to complete this task we rely on the recently developed modeling code GravityFM. We define a procedure to increase the contrast of the visible stellar clumps in images simulated with the abovementioned instruments and we attempt a statistical comparison of the detections. Secondly, we show how the images generated with our pipeline can be combined with other simulators, such as SimCADO image simulator for E-ELT/MICADO, which also includes the support from the Adaptive Optics system MORFEO
Quality of experience and access network traffic management of HTTP adaptive video streaming
The thesis focuses on Quality of Experience (QoE) of HTTP adaptive video streaming (HAS) and traffic management in access networks to improve the QoE of HAS. First, the QoE impact of adaptation parameters and time on layer was investigated with subjective crowdsourcing studies. The results were used to compute a QoE-optimal adaptation strategy for given video and network conditions. This allows video service providers to develop and benchmark improved adaptation logics for HAS. Furthermore, the thesis investigated concepts to monitor video QoE on application and network layer, which can be used by network providers in the QoE-aware traffic management cycle. Moreover, an analytic and simulative performance evaluation of QoE-aware traffic management on a bottleneck link was conducted. Finally, the thesis investigated socially-aware traffic management for HAS via Wi-Fi offloading of mobile HAS flows. A model for the distribution of public Wi-Fi hotspots and a platform for socially-aware traffic management on private home routers was presented. A simulative performance evaluation investigated the impact of Wi-Fi offloading on the QoE and energy consumption of mobile HAS.Die Doktorarbeit beschäftigt sich mit Quality of Experience (QoE) – der subjektiv empfundenen Dienstgüte – von adaptivem HTTP Videostreaming (HAS) und mit Verkehrsmanagement, das in Zugangsnetzwerken eingesetzt werden kann, um die QoE des adaptiven Videostreamings zu verbessern. Zuerst wurde der Einfluss von Adaptionsparameters und der Zeit pro Qualitätsstufe auf die QoE von adaptivem Videostreaming mittels subjektiver Crowdsourcingstudien untersucht. Die Ergebnisse wurden benutzt, um die QoE-optimale Adaptionsstrategie für gegebene Videos und Netzwerkbedingungen zu berechnen. Dies ermöglicht Dienstanbietern von Videostreaming verbesserte Adaptionsstrategien für adaptives Videostreaming zu entwerfen und zu benchmarken. Weiterhin untersuchte die Arbeit Konzepte zum Überwachen von QoE von Videostreaming in der Applikation und im Netzwerk, die von Netzwerkbetreibern im Kreislauf des QoE-bewussten Verkehrsmanagements eingesetzt werden können. Außerdem wurde eine analytische und simulative Leistungsbewertung von QoE-bewusstem Verkehrsmanagement auf einer Engpassverbindung durchgeführt. Schließlich untersuchte diese Arbeit sozialbewusstes Verkehrsmanagement für adaptives Videostreaming mittels WLAN Offloading, also dem Auslagern von mobilen Videoflüssen über WLAN Netzwerke. Es wurde ein Modell für die Verteilung von öffentlichen WLAN Zugangspunkte und eine Plattform für sozialbewusstes Verkehrsmanagement auf privaten, häuslichen WLAN Routern vorgestellt. Abschließend untersuchte eine simulative Leistungsbewertung den Einfluss von WLAN Offloading auf die QoE und den Energieverbrauch von mobilem adaptivem Videostreaming
Comparative evaluation of acoustic and electric signals of partial discharges
Failures of power electric components such as transformers and outages can lead to a huge economical loss in the electric power grid. One of the main parts of a power electric components is the insulation system, namely, insulation oil, impregnated pressboard and paper. Several methods exist for diagnostics of these insulation materials. Partial discharge (PD) measurement known as one of the main non-destructive monitoring systems of the insulation materials. However, it has been mainly done off-line in maintenance periods, and the existing on-line methods generally provide less information due to environment electric noises. In contrast to electric PD measurement system, the acoustic emission (AE) measurement system is well known for its immunity against environment electrical noises.
In this thesis comparative evaluation of acoustic and electric signals of PD events generated in oil impregnated pressboard and papers is investigated. The thesis is focused on the characteristic of PD activity and the consequence of that on the electric and AE signal. PD classification is defined by using the relation between acoustic and electric signals of PD events. Although the sensitivity of the AE sensors has been improved over the years, but the detection of the acoustic signals from PD activity in power equipment mainly transformers remain the main challenge of acoustic measurement. Lack of information regarding evaluation of electric PD signals and AE signals beside the mechanical attenuation are two main disadvantages of AE measurement method. Due to mechanical and electrical mechanism of waves generated during PD activities, the mechanical and electrical behaviour of the waves is discussed in more detail to have better understanding about the electric and acoustic signals. PD sources were generated at different electrode configurations such as needle-plane and electrode ball arrangement within a sample in the tank to investigate different types of PD. Electric characteristics of PD and different PD measuring technics such as electric, UHF and acoustic beside the mechanical behaviour of the acoustic waves are also discussed.
The corona in oil results regarding the relation between AE and electric PD signals shows the correlated behaviour between AE and PD apparent charge magnitude. However, in surface discharges these behaviours are uncorrelated. In this regards the surface discharge is studied in more detail, leading to the first results of PD with very low acoustic (no acoustic) activity. Regarding these results two different categories in term of AE signals of PDs are defined, silent PD and non-silent PD. Silent PDs are those PD activities without or with very low acoustic signal and non-silent PDs are with acoustic signal.
The existence of the silent PD is validated via oscilloscope and digital signal processing (DSP) devices. Also, with different innovative methods and arrangements such as needle plane and ball electrodes with and without oil gap, the probable reasons of creation this phenomenon (silent PD) is investigated.
It is found that the carbonization patterns start with non-silent PD and remain the same during silent PD activities even with very high electric apparent charges. It means the development in carbonization traces produce electric and AE signals and in contrast no changes in carbonization traces produce only electric signals with no AE signal. These results verify the advantages of using acoustic technics and electric measurement in terms of PD classification and localization.Ausfälle von Komponenten in elektrischen Energiesystemen wie Transformatoren können zu einem enormen wirtschaftlichen Verlust im Energiesystem führen. Einer der Hauptbestandteile der Komponenten in elektrischen Energiesystemen ist das Isoliersystem, nämlich Öl, imprägniert Pressboard und Papier. Es gibt mehrere Methoden zur Diagnose dieser Isoliermaterialien. Die Messung der Teilentladung (TE) ist als eines der wichtigsten zerstörungsfreien Überwachungssysteme für Isoliermaterialien bekannt. Jedoch wird dies in Wartungsperioden hauptsächlich offline durchgeführt, und die existierenden Online-Verfahren liefern im Allgemeinen weniger Informationen aufgrund von elektromagnetischen Störungen. Im Gegensatz zum elektrischen TE-Messsystem ist das Schallemissionsmesssystem für seine Immunität gegen elektrische Umgebungsgeräusche bekannt.
In dieser Arbeit wird die vergleichende Auswertung von akustischen und elektrischen Signalen von TE-Ereignissen untersucht, die in ölimprägnierten Pressboard und Papieren erzeugt werden. Sie konzentriert sich auf die Charakteristik der TE-Aktivität und deren Einfluss auf akustische Signale. Die TE-Klassifizierung wird definiert, indem die Beziehung zwischen akustischen und elektrischen Signalen von TE-Ereignissen verwendet wird. Obwohl die Empfindlichkeit der akustischen Sensoren im Laufe der Jahre verbessert wurde, bleibt die Erkennung der akustischen Signale von TE-Aktivität das Hauptproblem bei Komponenten in elektrischen Energiesystemen, hauptsächlich Transformatoren. Fehlende Informationen zur Auswertung von elektrischen TE-Signalen und akustischen Signalen sind neben der mechanischen Dämpfung zwei Hauptnachteile der akustischen Messung.
Wegen der mechanischen und elektrischen Mechanismen von Wellen, die während der TE-Aktivitäten erzeugt werden, wird deren Verhalten ausführlicher diskutiert, um ein besseres Verständnis über die elektrischen und akustischen Signale zu erhalten. An verschiedenen Elektrodenkonfigurationen innerhalb einer Probe im Öltank werden TE-Quellen an verschiedenen Elektrodenkonfigurationen wie Spitze-Platte und Elektrodenkugelanordnung innerhalb einer Probe im Tank erzeugt, um verschiedene Arten von TE zu untersuchen. Neben dem mechanischen Verhalten der akustischen Wellen werden auch elektrische Eigenschaften von TE und verschiedene TE-Messtechniken wie elektrisch, UHF und akustisch behandelt.
Die Ergebnisse bezüglich des Verhältnisses zwischen AE- und elektrischen TE-Signalen für Korona im Öl zeigen das korrelierte Verhalten zwischen AE- und TE-Signalen. Bei Oberflächenentladungen sind diese Verhaltensweisen jedoch unkorreliert. Die Oberflächenentladung wird genauer untersucht, was zu den ersten Ergebnissen von TE mit sehr geringer akustischer (keine akustischen Signale) Aktivität führt. In Bezug auf diese Ergebnisse werden zwei verschiedene Kategorien in Bezug auf elektrische und AE-Signale von TE definiert, stille TE und nicht-stille TE. Stille TE sind elektrische TE-Signale ohne oder mit sehr geringer akustischer Aktivität, und nicht-stille TE sind elektrische TE-Signale mit akustischer Aktivität.
Die Existenz der stillen PD wird über Oszilloskope und digitale Signalverarbeitungsgeräte (DSP) validiert. Auch mit verschiedenen innovativen Methoden und Anordnungen wie Nadel und Kugelelektroden mit und ohne Ölspalt werden die wahrscheinlichen Entstehungsursachen dieses Phänomens (Silent TE) untersucht.
Es wurde festgestellt, dass die Karbonisierungsmuster mit nicht-stiller TE beginnen und während stiller TE-Aktivitäten selbst bei sehr hohen scheinbaren elektrischen Ladungen unverändert bleiben. Dies bedeutet, dass bei der Entwicklung der Karbonisierungsspuren elektrische und AE-Signale erzeugt werden und im Gegensatz dazu ohne Änderungen der Karbonisierungsspuren nur elektrische Signale (ohne AE-Signale) erzeugt werden. Diese Differenzierung ist nur möglich bei gleichzeitigem Einsatz der akustischen Technik und elektrischen Messung im Hinblick auf die TE-Klassifizierung und Lokalisierung
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