Aerospace medicine and biology: A continuing bibliography with indexes (supplement 299)

This bibliography lists 96 reports, articles, and other documents introduced into the NASA scientific and technical information system in June, 1987

A continued learning approach for model-informed precision dosing: Updating models in clinical practice

Model-informed precision dosing (MIPD) is a quantitative dosing framework that combines prior knowledge on the drug-disease-patient system with patient data from therapeutic drug/ biomarker monitoring (TDM) to support individualized dosing in ongoing treatment. Structural models and prior parameter distributions used in MIPD approaches typically build on prior clinical trials that involve only a limited number of patients selected according to some exclusion/inclusion criteria. Compared to the prior clinical trial population, the patient population in clinical practice can be expected to also include altered behavior and/or increased interindividual variability, the extent of which, however, is typically unknown. Here, we address the question of how to adapt and refine models on the level of the model parameters to better reflect this real-world diversity. We propose an approach for continued learning across patients during MIPD using a sequential hierarchical Bayesian framework. The approach builds on two stages to separate the update of the individual patient parameters from updating the population parameters. Consequently, it enables continued learning across hospitals or study centers, because only summary patient data (on the level of model parameters) need to be shared, but no individual TDM data. We illustrate this continued learning approach with neutrophil-guided dosing of paclitaxel. The present study constitutes an important step toward building confidence in MIPD and eventually establishing MIPD increasingly in everyday therapeutic use

Aerospace medicine and biology: A continuing bibliography with indexes

This bibliography lists 138 reports, articles, and other documents introduced into the NASA scientific and technical information system in Jun. 1980

Aerospace Medicine and Biology: A continuing bibliography with indexes, supplement 212

A bibliography listing 146 reports, articles, and other documents introduced into the NASA scientific and technical information system is presented. The subject coverage concentrates on the biological, psychological, and environmental factors involved in atmospheric and interplanetary flight. Related topics such as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, and exobiology are also given attention

Bayesian Multi-Model Frameworks - Properly Addressing Conceptual Uncertainty in Applied Modelling

We use models to understand or predict a system. Often, there are multiple plausible but competing model concepts. Hence, modelling is associated with conceptual uncertainty, i.e., the question about proper handling of such model alternatives. For mathematical models, it is possible to quantify their plausibility based on data and rate them accordingly. Bayesian probability calculus offers several formal multi-model frameworks to rate models in a finite set and to quantify their conceptual uncertainty as model weights. These frameworks are Bayesian model selection and averaging (BMS/BMA), Pseudo-BMS/BMA and Bayesian Stacking. The goal of this dissertation is to facilitate proper utilization of these Bayesian multi-model frameworks. They follow different principles in model rating, which is why derived model weights have to be interpreted differently, too. These principles always concern the model setting, i.e., how the models in the set relate to one another and the true model of the system that generated observed data. This relation is formalized in model scores that are used for model weighting within each framework. The scores resemble framework-specific compromises between the ability of a model to fit the data and the therefore required model complexity. Hence, first, the scores are investigated systematically regarding their respective take on model complexity and are allocated in a developed classification scheme. This shows that BMS/BMA always pursues to identify the true model in the set, that Pseudo-BMS/BMA searches the model with largest predictive power despite none of the models being the true one, and that, on that condition, Bayesian Stacking seeks reliability in prediction by combining predictive distributions of multiple models. An application example with numerical models illustrates these behaviours and demonstrates which misinterpretations of model weights impend, if a certain framework is applied despite being unsuitable for the underlying model setting. Regarding applied modelling, first, a new setting is proposed that allows to identify a ``quasi-true'' model in a set. Second, Bayesian Bootstrapping is employed to take into account that rating of predictive capability is based on only limited data. To ensure that the Bayesian multi-model frameworks are employed properly and goal-oriented, a guideline is set up. With respect to a clearly defined modelling goal and the allocation of available models to the respective setting, it leads to the suitable multi-model framework. Aside of the three investigated frameworks, this guideline further contains an additional one that allows to identify a (quasi-)true model if it is composed of a linear combination of the model alternatives in the set. The gained insights enable a broad range of users in science practice to properly employ Bayesian multi-model frameworks in order to quantify and handle conceptual uncertainty. Thus, maximum reliability in system understanding and prediction with multiple models can be achieved. Further, the insights pave the way for systematic model development and improvement.Wir benutzen Modelle, um ein System zu verstehen oder vorherzusagen. Oft gibt es dabei mehrere plausible aber konkurrierende Modellkonzepte. Daher geht Modellierung einher mit konzeptioneller Unsicherheit, also der Frage nach dem angemessenen Umgang mit solchen Modellalternativen. Bei mathematischen Modellen ist es möglich, die Plausibilität jedes Modells anhand von Daten des Systems zu quantifizieren und Modelle entsprechend zu bewerten. Bayes'sche Wahrscheinlichkeitsrechnung bietet dazu verschiedene formale Multi-Modellrahmen, um Modellalternativen in einem endlichen Set zu bewerten und ihre konzeptionelle Unsicherheit als Modellgewichte zu beziffern. Diese Rahmen sind Bayes'sche Modellwahl und -mittelung (BMS/BMA), Pseudo-BMS/BMA und Bayes'sche Modellstapelung. Das Ziel dieser Dissertation ist es, den adäquaten Umgang mit diesen Bayes'schen Multi-Modellrahmen zu ermöglichen. Sie folgen unterschiedlichen Prinzipien in der Modellbewertung weshalb die abgeleiteten Modellgewichte auch unterschiedlich zu interpretieren sind. Diese Prinzipien beziehen sich immer auf das Modellsetting, also darauf, wie sich die Modelle im Set zueinander und auf das wahre Modell des Systems beziehen, welches bereits gemessene Daten erzeugt hat. Dieser Bezug ist in Kenngrößen formalisiert, die innerhalb jedes Rahmens der Modellgewichtung dienen. Die Kenngrößen stellen rahmenspezifische Kompromisse dar, zwischen der Fähigkeit eines Modells die Daten zu treffen und der dazu benötigten Modellkomplexität. Daher werden die Kenngrößen zunächst systematisch auf ihre jeweilige Bewertung von Modellkomplexität untersucht und in einem entsprechend entwickelten Klassifikationschema zugeordnet. Dabei zeigt sich, dass BMS/BMA stets verfolgt das wahre Modell im Set zu identifizieren, dass Pseudo-BMS/BMA das Modell mit der höchsten Vorsagekraft sucht, obwohl kein wahres Modell verfügbar ist, und dass Bayes'sche Modellstapelung unter dieser Bedingung Verlässlichkeit von Vorhersagen anstrebt, indem die Vorhersageverteilungen mehrerer Modelle kombiniert werden. Ein Anwendungsbeispiel mit numerischen Modellen verdeutlicht diese Verhaltenweisen und zeigt auf, welche Fehlinterpretationen der Modellgewichte drohen, wenn ein bestimmter Rahmen angewandt wird, obwohl er nicht zum zugrundeliegenden Modellsetting passt. Mit Bezug auf anwendungsorientierte Modellierung wird dabei erstens ein neues Setting vorgestellt, das es ermöglicht, ein ``quasi-wahres'' Modell in einem Set zu identifizieren. Zweitens wird Bayes'sches Bootstrapping eingesetzt um bei der Bewertung der Vorhersagegüte zu berücksichtigen, dass diese auf Basis weniger Daten erfolgt. Um zu gewährleisten, dass die Bayes'schen Multi-Modellrahmen angemessen und zielführend eingesetzt werden, wird schließlich ein Leitfaden erstellt. Anhand eines klar definierten Modellierungszieles und der Einordnung der gegebenen Modelle in das entspechende Setting leitet dieser zum geeigneten Multi-Modellrahmen. Neben den drei untersuchten Rahmen enthält dieser Leitfaden zudem einen weiteren, der es ermöglicht ein (quasi-)wahres Modell zu identifizieren, wenn dieses aus einer Linearkombination der Modellalternativen im Set besteht. Die gewonnenen Erkenntnisse ermöglichen es einer breiten Anwenderschaft in Wissenschaft und Praxis, Bayes'sche Multi-Modellrahmen zur Quantifizierung und Handhabung konzeptioneller Unsicherheit adäquat einzusetzen. Dadurch lässt sich maximale Verlässlichkeit in Systemverständis und -vorhersage durch mehrere Modelle erreichen. Die Erkenntnisse ebnen darüber hinaus den Weg für systematische Modellentwicklung und -verbesserung

Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4-8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions

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/