1,420 research outputs found

    Investigating the role of versican in immune exclusion in triple negative breast cancer

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    Triple negative breast cancer has the highest T cell infiltrate in comparison to other subtypes of breast cancer. To try to improve the anti-tumour response of these T cells, immunotherapy has been trialled, however clinical trials showed poor results. The response to immunotherapy in solid tumours is limited and this has been attributed to the presence of the extracellular matrix (ECM). The ECM can interact with T cells biochemically or physically, affecting their trafficking in the tumour. This can cause the restriction of T cells in the stroma limiting their contact with the tumour epithelial cells, leading to an immune excluded phenotype. Identifying key components of the ECM that are associated with the restriction of immune cells can provide potential targets that could be degraded to improve anti-tumour immunity. From previous work in the lab a signature of molecules were identified which were associated with immunosuppression. In the initial analysis of these molecules in a subset of TNBC tissues, versican (VCAN) was identified as an ECM component that associates with immune cell infiltration into the tumour epithelium. VCAN is a proteoglycan which has the glycosaminoglycan chondroitin sulphate (CS) attached to the peptide backbone. Through its multiple domains and glycan post-translational modifications, VCAN has been shown to have a role in inflammation and cancer progression. To study how VCAN may affect the trafficking of T cells, I first looked at how VCAN expression associated with immune excluded tissues. It was observed that VCAN levels were higher in the epithelial zone of excluded tissues compared to inflamed tissues. CS levels were then explored within the tissues where the sulphation patterns on CS in the stroma led to the discovery of CS-C being higher in excluded tissues and CS-A being higher in inflamed tissues. To observe this effect in-vitro, VCAN was enriched from TNBC and fibroblast cell line secretions. The effect of CS was tested through chondroitinase (CSase) treatment of VCAN enriched protein in a transwell model. An increase in invasion was observed following CSase treatment of protein with high levels of CS-C. To conclude, from the study I identified that within TNBC tissues the excluded immune phenotype associates with epithelial zone expressed VCAN which has a different CS sulphation pattern compared to inflamed tissues, and this difference in sulphation inhibits T-cell trafficking in in vitro models, which can be overcome through enzymatic digestion of the CS. Therefore, targeting VCAN by degrading CS may provide a way to drive excluded tumours into an inflamed and therapy responsive phenotype. Such an approach could be coupled with immunotherapy such as cell-based T-cell therapies

    Analysis and monitoring of single HaCaT cells using volumetric Raman mapping and machine learning

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    No explorer reached a pole without a map, no chef served a meal without tasting, and no surgeon implants untested devices. Higher accuracy maps, more sensitive taste buds, and more rigorous tests increase confidence in positive outcomes. Biomedical manufacturing necessitates rigour, whether developing drugs or creating bioengineered tissues [1]–[4]. By designing a dynamic environment that supports mammalian cells during experiments within a Raman spectroscope, this project provides a platform that more closely replicates in vivo conditions. The platform also adds the opportunity to automate the adaptation of the cell culture environment, alongside spectral monitoring of cells with machine learning and three-dimensional Raman mapping, called volumetric Raman mapping (VRM). Previous research highlighted key areas for refinement, like a structured approach for shading Raman maps [5], [6], and the collection of VRM [7]. Refining VRM shading and collection was the initial focus, k-means directed shading for vibrational spectroscopy map shading was developed in Chapter 3 and exploration of depth distortion and VRM calibration (Chapter 4). “Cage” scaffolds, designed using the findings from Chapter 4 were then utilised to influence cell behaviour by varying the number of cage beams to change the scaffold porosity. Altering the porosity facilitated spectroscopy investigation into previously observed changes in cell biology alteration in response to porous scaffolds [8]. VRM visualised changed single human keratinocyte (HaCaT) cell morphology, providing a complementary technique for machine learning classification. Increased technical rigour justified progression onto in-situ flow chamber for Raman spectroscopy development in Chapter 6, using a Psoriasis (dithranol-HaCaT) model on unfixed cells. K-means-directed shading and principal component analysis (PCA) revealed HaCaT cell adaptations aligning with previous publications [5] and earlier thesis sections. The k-means-directed Raman maps and PCA score plots verified the drug-supplying capacity of the flow chamber, justifying future investigation into VRM and machine learning for monitoring single cells within the flow chamber

    AI in drug discovery and its clinical relevance

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    The COVID-19 pandemic has emphasized the need for novel drug discovery process. However, the journey from conceptualizing a drug to its eventual implementation in clinical settings is a long, complex, and expensive process, with many potential points of failure. Over the past decade, a vast growth in medical information has coincided with advances in computational hardware (cloud computing, GPUs, and TPUs) and the rise of deep learning. Medical data generated from large molecular screening profiles, personal health or pathology records, and public health organizations could benefit from analysis by Artificial Intelligence (AI) approaches to speed up and prevent failures in the drug discovery pipeline. We present applications of AI at various stages of drug discovery pipelines, including the inherently computational approaches of de novo design and prediction of a drug's likely properties. Open-source databases and AI-based software tools that facilitate drug design are discussed along with their associated problems of molecule representation, data collection, complexity, labeling, and disparities among labels. How contemporary AI methods, such as graph neural networks, reinforcement learning, and generated models, along with structure-based methods, (i.e., molecular dynamics simulations and molecular docking) can contribute to drug discovery applications and analysis of drug responses is also explored. Finally, recent developments and investments in AI-based start-up companies for biotechnology, drug design and their current progress, hopes and promotions are discussed in this article.  Other InformationPublished in:HeliyonLicense: https://creativecommons.org/licenses/by/4.0/See article on publisher's website: https://doi.org/10.1016/j.heliyon.2023.e17575 </p

    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

    Model-based deep autoencoders for clustering single-cell RNA sequencing data with side information

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    Clustering analysis has been conducted extensively in single-cell RNA sequencing (scRNA-seq) studies. scRNA-seq can profile tens of thousands of genes\u27 activities within a single cell. Thousands or tens of thousands of cells can be captured simultaneously in a typical scRNA-seq experiment. Biologists would like to cluster these cells for exploring and elucidating cell types or subtypes. Numerous methods have been designed for clustering scRNA-seq data. Yet, single-cell technologies develop so fast in the past few years that those existing methods do not catch up with these rapid changes and fail to fully fulfil their potential. For instance, besides profiling transcription expression levels of genes, recent single-cell technologies can capture other auxiliary information at the single-cell level, such as protein expression (multi-omics scRNA-seq) and cells\u27 spatial location information (spatial-resolved scRNA-seq). Most existing clustering methods for scRNA-seq are performed in an unsupervised manner and fail to exploit available side information for optimizing clustering performance. This dissertation focuses on developing novel computational methods for clustering scRNA-seq data. The basic models are built on a deep autoencoder (AE) framework, which is coupled with a ZINB (zero-inflated negative binomial) loss to characterize the zero-inflated and over-dispersed scRNA-seq count data. To integrate multi-omics scRNA-seq data, a multimodal autoencoder (MAE) is employed. It applies one encoder for the multimodal inputs and two decoders for reconstructing each omics of data. This model is named scMDC (Single-Cell Multi-omics Deep Clustering). Besides, it is expected that cells in spatial proximity tend to be of the same cell types. To exploit cellular spatial information available for spatial-resolved scRNA-seq (sp-scRNA-seq) data, a novel model, DSSC (Deep Spatial-constrained Single-cell Clustering), is developed. DSSC integrates the spatial information of cells into the clustering process by two steps: 1) the spatial information is encoded by using a graphical neural network model; 2) cell-to-cell constraints are built based on the spatially expression pattern of the marker genes and added in the model to guide the clustering process. DSSC is the first model which can utilize the information from both the spatial coordinates and the marker genes to guide the cell/spot clustering. For both scMDC and DSSC, a clustering loss is optimized on the bottleneck layer of autoencoder along with the learning of feature representation. Extensive experiments on both simulated and real datasets demonstrate that scMDC and DSSC boost clustering performance significantly while costing no extra time and space during the training process. These models hold great promise as valuable tools for harnessing the full potential of state-of-the-art single-cell data

    Gut-brain interactions affecting metabolic health and central appetite regulation in diabetes, obesity and aging

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    The central aim of this thesis was to study the effects of gut microbiota on host energy metabolism and central regulation of appetite. We specifically studied the interaction between gut microbiota-derived short-chain fatty acids (SCFAs), postprandial glucose metabolism and central regulation of appetite. In addition, we studied probable determinants that affect this interaction, specifically: host genetics, bariatric surgery, dietary intake and hypoglycemic medication.First, we studied the involvement of microbiota-derived short-chain fatty acids in glucose tolerance. In an observational study we found an association of intestinal availability of SCFAs acetate and butyrate with postprandial insulin and glucose responses. Hereafter, we performed a clinical trial, administering acetate intravenously at a constant rate and studied the effects on glucose tolerance and central regulation of appetite. The acetate intervention did not have a significant effect on these outcome measures, suggesting the association between increased gastrointestinal SCFAs and metabolic health, as observed in the observational study, is not paralleled when inducing acute plasma elevations.Second, we looked at other determinants affecting gut-brain interactions in metabolic health and central appetite signaling. Therefore, we studied the relation between the microbiota and central appetite regulation in identical twin pairs discordant for BMI. Second, we studied the relation between microbial composition and post-surgery gastrointestinal symptoms upon bariatric surgery. Third, we report the effects of increased protein intake on host microbiota composition and central regulation of appetite. Finally, we explored the effects of combination therapy with GLP-1 agonist exenatide and SGLT2 inhibitor dapagliflozin on brain responses to food stimuli

    Development and application of new machine learning models for the study of colorectal cancer

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    En la actualidad, en el ámbito sanitario, hay un interés creciente en la consideración de técnicas de Inteligencia Artificial, en concreto técnicas de Aprendizaje Automático o Machine Learning, que tan buenos resultados están proporcionando desde hace tiempo en diferentes ámbitos, como la industria, el comercio electrónico, la educación, etc. Sin embargo, en el ámbito de la sanidad hay un reto aún mayor ya que, además de necesitar sistemas muy probados, puesto que sus resultados van a repercutir directamente en la salud de las personas, también es necesario alcanzar un buen equilibrio en cuanto a interpretabilidad. Esto es de gran importancia ya que, actualmente, con métodos de caja negra, que pueden llegar a ser muy precisos, es difícil saber qué motivó que el sistema automático tomara una decisión y no otra. Esto puede generar rechazo entre los profesionales sanitarios debido a la inseguridad que pueden llegar a sentir por no poder explicar una decisión clínica tomada en base a un sistema de apoyo a la toma de decisiones. En este contexto, desde el primer momento establecimos que la interpretabilidad de los resultados debía ser una de las premisas que gobernara transversalmente todo el trabajo que se desarrollara en esta tesis doctoral. En este sentido, todos los desarrollos realizados generan bien árboles de clasificación (los cuales dan lugar a reglas interpretables) o bien reglas de asociación que describen relaciones entre los datos existentes. Por otro lado, el cáncer colorrectal es una neoplasia maligna con una alta morbimortalidad tanto en hombres como en mujeres. Esta requiere, indiscutiblemente, de una atención multidisciplinar en la que diferentes profesionales sanitarios (médicos de familia, gastroenterólogos, radiólogos, cirujanos, oncólogos, farmacéuticos, personal de enfermería, etc.) realicen un abordaje conjunto de la patología para ofrecer la mejor atención posible al paciente. Pero además, en adelante, sería muy interesante incorporar a científicos de datos en ese equipo multidisciplinar, ya que se puede sacar un gran partido a toda la información que se genera diariamente sobre esta patología. En esta tesis doctoral se ha planteado, precisamente, el estudio de un conjunto de datos de pacientes con cáncer colorrectal con un un conjunto de técnicas de inteligencia artificial y el desarrollo de nuevos modelos de aprendizaje automático para el mismo. Los resultados han sido los que se exponen a continuación: Una revisión bibliográfica sobre el uso de Machine Learning aplicado a cáncer colorrectal, a partir de la cual se ha realizado una taxonomía de los trabajos existentes a fecha de realización del estudio del estado del arte. Esta taxonomía clasifica los diferentes trabajos estudiados atendiendo a diferentes criterios como son el tipo de dataset utilizado, el tipo de algoritmo implementado, el tamaño del dataset y su disponibilidad pública, el uso o no de algoritmos de selección de características y el uso o no de técnicas de extracción de características. Un modelo de extracción de reglas de asociación de clases con la intención de entender mejor por qué algunos pacientes podrían sufrir complicaciones tras una intervención quirúrgica o recidivas de su cáncer. Este trabajo ha dado lugar a una metodología para la obtención de descripciones interpretables y manejables (es importante que las reglas generadas tengan un tamaño reducido de manera que así sea útil para los sanitarios). Un modelo de selección de características y de instancias para poder inducir mejores árboles de clasificación. Un algoritmo de Evolución Gramatical para inducir una gran variedad de árboles de clasificación tan precisos como los obtenidos por los conocidos métodos C4.5 y CART. En este caso, se ha utilizado la librería PonyGE2 de Python y, debido a su escasa especificidad para aplicación a nuestro problema, se han desarrollado una serie de operadores que permiten inducir árboles más interpretables en comparación con los que produce PonyGE2 de forma estándar. Los resultados obtenidos en cada uno de los desarrollos realizados se han comparado con los resultados proporcionados por métodos existentes en la literatura y de reconocido prestigio, tanto del campo de la clasificación como del campo de la minería de reglas de asociación, demostrándose una mejor adaptación de nuestros modelos a las características que presentaba el conjunto de datos de estudio, y que pueden ser de aplicación a otros casos.Today, in healthcare, there is a growing interest in considering Artificial Intelligence techniques, specifically Machine Learning techniques, which have been providing good results in different fields such as industry, e‑commerce, education, etc., since a long time ago. However, in the field of healthcare there is an even greater challenge because it is needed both highly tested systems, since their results will have a direct impact on people's health, and a good level in terms of interpretability. This is very important since with black box methods, which can be very precise, it will be dificult to know what motivated the automatic system to take one decision or any other. This fact can generate rejection among healthcare professionals due to the insecurity they may feel because they cannot explain a clinical decision taken on the basis of a decision support system. In this context, from the very begining we established that the interpretability of the results should be one of the premises leading all the work carried out in this doctoral thesis. In this sense, all the developments carried out generate either classification trees (which produce interpretable rules) or association rules that describe relationships between existing data. On the other hand, colorectal cancer is a malignant neoplasia with a high morbidity and mortality rate in both men and women, which unquestionably requires multidisciplinary care in which different healthcare professionals (family doctors, gastroenterologists, radiologists, surgeons, oncologists, pharmacists, nursing staff, etc.) take a joint approach to the pathology in order to offer the best possible care to the patient. But it would also be very interesting to incorporate data scientists into this multidisciplinary team in the future, as they can make the most of all the information that is generated on this pathology daily. In this doctoral thesis, it has been proposed the study of a dataset of patients with colorectal cancer with a set of artificial intelligence techniques and the development of new machine learning models for it. The results are shown below: A literature review on the use of Machine Learning applied to colorectal cancer, from which a taxonomy of the existing works has been produced. This taxonomy classifies the different works of the state‑of‑the‑arte according to different criterio such as the type of dataset that has been used, the type of algorithm that has been implemented, the size of the dataset and its public availability, the use or not of feature selection algorithms and the use or not of feature extraction techniques. A class association rule extraction model with the intention of better understanding why some patients might experience complications after surgery or recurrence of their cancer. This work has given rise to a methodology for obtaining interpretable and manageable descriptions (it is important that the generated rules have a reduced size so that they are useful for practitioners). A feature and instance selection model to induce better classification trees. A Grammatical Evolution algorithm to induce a wide variety of classification trees as accurate as those obtained by the well‑known C4.5 and CART methods. In this case, the PonyGE2 Python library has been used and, due to its low specificity for application to our problem, a series of operators have been developed, which allow inducing more interpretable trees compared to those produced by PonyGE2 in a standard way. The results obtained in each of the developments carried out have been compared with the results provided by well known methods existing in the literature, both in the field of classification and in the field of association rule mining, demonstrating a better fit of our models to the features of the dataset, which can be applied to other cases. great efficiency in our models. This demonstrates that it is possible to reach a good balance between precision and interpretability

    Exponential power mixture model for regression : estimation and variable selection

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    The mixture regression model is an important technique used in statistical modelling to investigate the relationship between variables. It has been applied in many fields such as genetics, finance and biology. In this research, we focus on its application to genetic data. As we know gene expression data normally contains unknown correlation structures even after normalization, hence it raises a great challenge for the existing clustering methods such as the Gaussian mixture(GM) model and k-mean. Here we use the exponential power distribution to robustly overcome the clustering of gene expression data by treating the data as a mixture of regression. The exponential power distribution (EPD) is a scale mixture of Gaussian distributions that has varying shape parameters. In this study we introduce and develop our method based on two different aspects of multiple regression with random errors distributed according to the exponential power distribution. The first aspect is estimation: we use both the ExpectationMaximisation algorithm (EM) and the Newton-Raphson method to estimate the parameters of the exponential power distribution mixture regression models. The second aspect is simultaneous variable selection and clustering: we develop a LASSO-type method to select only the related variables in a large dataset, especially for a high dimensional dataset. The novelty of this research regarding to the Expectation-Maximization algorithm is that we convert each penalised mixture regression estimation problem to a LASSO (Least absolute shrinkage and selection operator) problem. The performance of our method is assessed on both independent and dependent data. We also compared the EPD mixture regression with Gaussian mixture regressions by simulations and real data analyses. We also derive the model selection criteria such as AIC, BIC and EBIC for both EPD mixture and GM models

    Spatiotemporal analysis of transcription dynamics

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