1,262 research outputs found
The ins and outs of open-angle Glaucoma:drugs, diet, and defecation
Glaucoma is the leading cause of irreversible blindness and second leading cause of blindness. The primary aim of this thesis is to provide insight into the role of systemic effectsin the pathophysiology of OAG.<br/
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/
Analytical validation of innovative magneto-inertial outcomes: a controlled environment study.
peer reviewe
4D FLOW CMR in congenital heart disease
This thesis showed that the use of a cloud-based reconstruction applicationwith advanced eddy currents correction, integrated with interactiveimaging evaluation tools allowed for remote visualization and interpretationof 4D flow data and that was sufficient for gross visualizationof aortic valve regurgitation. Further, this thesis demonstrated that bulkflow and pulmonary regurgitation can be accurately quantified using 4Dflow imaging analyzed. Peak systolic velocity over the pulmonary valvemay be underestimated. However, the measurement of peak systolicvelocity can be optimized if measured at the level of highest velocity inthe pulmonary artery. Also correlated against invasive measurements (inan animal model), this thesis shows that aorta flow and pulmonary flowcan be accurately and simultaneously measured by 4D flow MRI.When applied in clinical practice, 4D flow has extra advantages, of beingable to visualize flow pattern, vorticity and to predict aortic growth. InASD patients it can measure shunt volume directly following the septumframe by frame. In Fontan patients in can visualize better than standardMRI the Fontan circuit and it can measure flow at multiple points alongthe Fontan circuit. We observed in our Fontan population that shunt lesionswere very common, most of the time via veno-venous collaterals.Further using advanced computations, we showed that WSS angle wasthe only independent predictor of aortic growth in BAV patients. We alsoshowed the feasibility of GLS analysis on 4D flow MRI and presented anintegrative approach in which flow and functional data are acquired inone sequence.From the technical point of view, 4D flow MRI has proved to complementthe traditional components of the standard cardiac MR exams, enablingin-depth insights into hemodynamics. At this moment it proved its addedvalue, but in most of the cases it is not able yet to replace the standardexam. This is still due to long scanning times and relatively longpost-processing times.<br/
30th European Congress on Obesity (ECO 2023)
This is the abstract book of 30th European Congress on Obesity (ECO 2023
The optimal connection model for blood vessels segmentation and the MEA-Net
Vascular diseases have long been regarded as a significant health concern.
Accurately detecting the location, shape, and afflicted regions of blood
vessels from a diverse range of medical images has proven to be a major
challenge. Obtaining blood vessels that retain their correct topological
structures is currently a crucial research issue. Numerous efforts have sought
to reinforce neural networks' learning of vascular geometric features,
including measures to ensure the correct topological structure of the
segmentation result's vessel centerline. Typically, these methods extract
topological features from the network's segmentation result and then apply
regular constraints to reinforce the accuracy of critical components and the
overall topological structure. However, as blood vessels are three-dimensional
structures, it is essential to achieve complete local vessel segmentation,
which necessitates enhancing the segmentation of vessel boundaries.
Furthermore, current methods are limited to handling 2D blood vessel
fragmentation cases. Our proposed boundary attention module directly extracts
boundary voxels from the network's segmentation result. Additionally, we have
established an optimal connection model based on minimal surfaces to determine
the connection order between blood vessels. Our method achieves
state-of-the-art performance in 3D multi-class vascular segmentation tasks, as
evidenced by the high values of Dice Similarity Coefficient (DSC) and
Normalized Surface Dice (NSD) metrics. Furthermore, our approach improves the
Betti error, LR error, and BR error indicators of vessel richness and
structural integrity by more than 10% compared to other methods, and
effectively addresses vessel fragmentation and yields blood vessels with a more
precise topological structure.Comment: 19 page
Modern meat: the next generation of meat from cells
Modern Meat is the first textbook on cultivated meat, with contributions from over 100 experts within the cultivated meat community.
The Sections of Modern Meat comprise 5 broad categories of cultivated meat: Context, Impact, Science, Society, and World.
The 19 chapters of Modern Meat, spread across these 5 sections, provide detailed entries on cultivated meat. They extensively tour a range of topics including the impact of cultivated meat on humans and animals, the bioprocess of cultivated meat production, how cultivated meat may become a food option in Space and on Mars, and how cultivated meat may impact the economy, culture, and tradition of Asia
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