1,514 research outputs found

    The effect of autologous macrophage therapy in cirrhosis in response to individual immune reparative pathways: developing a novel therapy

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    BACKGROUND: Liver cirrhosis is the end stage of any injury process to the liver. Once established it inevitably progresses to complications such as portal hypertension, cancer and death. There is not cure for liver cirrhosis besides liver transplant. We face an unmet demand for treatment of this condition. The role of macrophages in fibrosis development and resolution in the liver has been extensively investigated. Prof Forbes group invested in the development of autologous macrophage product to promote fibrosis resolution hence cirrhosis regression. This has demonstrated its efficacy and safety in animal models. From these encouraging pre-clinic data a phase 1 first in human clinical trial of autologous activated macrophage product for cirrhotic patients was developed. METHODS: Using an established 3+3 dose escalation model we enrolled a total of 9 subject in the phase 1 trial reaching a maximum achieved and safe dose of 1x10^9 macrophages. In addition to adverse events, dose toxicity and macrophage activation syndrome (MAS) parameter, we evaluated a varied range of circulating cytokines and chemokine pre and post treatment using a commercial kit. Moreover we developed a protocol for P13- magnetic resonance spectrometry (MRS) for the analysis of the metabolically active liver parenchyma. Data from the phase 1 trial were used to improve the autologous cellular produce and phase 2 randomised controlled trial. RESULTS: The autologous activated macrophage produce is demonstrated not to cause any toxicity in this first in human study of cirrhotic population of different aetiology. Cytokine and chemokine analysis supports these findings and specifically demonstrates low levels of IL-8, which represent cardinal feature of MAS. Other interesting cytokine signals may support extra cellular matrix remodelling effect of the autologous macrophage product infusion. In addition we demonstrated a reproducible protocol for MRS in liver disease. DISCUSSION: Autologous activated macrophage infusion did not result in any toxicity in cirrhotic subjects taking part in this study and shows preliminary signs of efficacy in fibrosis resolution both clinically and biochemically. This work places the basis of development of cellular products for treatment of cirrhosis and fibrosis and provides invaluable insight in immune response to cellular treatment

    Genomic insights for safety assessment of foodborne bacteria.

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    La sicurezza alimentare e l'accesso ad essa sono fondamentali per sostenere la vita e promuovere una buona salute. Gli alimenti non sicuri, contenenti microrganismi o sostanze chimiche nocive, sono causa di oltre 200 malattie, dalla diarrea al cancro, che colpiscono in particolare i neonati, i bambini piccoli, gli anziani e gli individui immunocompromessi. L'onere globale delle malattie di origine alimentare si ripercuote sulla salute pubblica, sulla società e sull'economia, pertanto è necessaria una buona collaborazione tra governi, produttori e consumatori per contribuire a garantire la sicurezza alimentare e sistemi alimentari più solidi. L'indagine più recente condotta dall'OMS (2015) ha evidenziato una stima di 600 milioni di individui malati e 420.000 decessi annui associati ad alimenti non sicuri. L'impatto economico è dovuto principalmente alla mancanza di alimenti sicuri nei Paesi a basso e medio reddito, con una perdita di 110 miliardi di dollari l'anno in termini di produttività e spese mediche. Le sfide principali per garantire la sicurezza alimentare rimangono legate alla nostra produzione alimentare e alla catena di approvvigionamento, dove fattori come la contaminazione ambientale, le preferenze dei consumatori, il rilevamento tempestivo e la sorveglianza dei focolai giocano un ruolo cruciale. Recentemente, le metodologie basate sul DNA per il rilevamento e l'indagine microbica hanno suscitato particolare interesse, soprattutto grazie allo sviluppo delle tecnologie di sequenziamento. Contrariamente ai metodi tradizionali dipendenti dalla coltura, le tecniche basate sul DNA, come il sequenziamento dell'intero genoma (WGS), mirano a risultati rapidi e sensibili a un prezzo relativamente basso e a tempi di elaborazione brevi. Inoltre, il WGS conferisce un elevato potere discriminatorio che consente di determinare importanti caratteristiche genomiche legate alla sicurezza alimentare, come la tassonomia, il potenziale patogeno, la virulenza e la resistenza antimicrobica e il relativo trasferimento genetico. La comprensione di queste caratteristiche è fondamentale per progettare strategie di rilevamento e mitigazione da applicare lungo l'intera catena alimentare secondo una prospettiva di "One Health", che porta ad acquisire conoscenze sul microbiota che influenza l'uomo, gli animali e l'ambiente. Lo scopo della tesi è quello di approfondire la genomica dei microbi di origine alimentare per la loro caratterizzazione e per creare o migliorare le strategie per la loro individuazione e i metodi di mitigazione. In particolare, questa tesi si concentra sulla valutazione del potenziale patogeno sulla base di analisi genomiche che includono studi di tassonomia, virulenza, resistenza agli antibiotici e mobiloma. Il secondo obiettivo è quello di trarre vantaggio dalle conoscenze genomiche per progettare dispositivi di rilevamento rapidi ed efficaci e metodi di mitigazione affidabili per affrontare i patogeni di origine alimentare. Più in dettaglio, saranno trattati i seguenti argomenti: La presenza di ceppi multiresistenti negli alimenti fermentati pronti al consumo rappresenta un rischio per la salute pubblica per la diffusione di determinanti AMR nella catena alimentare e nel microbiota intestinale dei consumatori. Le analisi genomiche hanno permesso di valutare accuratamente la sicurezza del ceppo UC7251 di E. faecium, in relazione alla sua virulenza e alla co-localizzazione dei geni di resistenza agli antibiotici e ai metalli pesanti in elementi mobili con capacità di coniugazione in diverse matrici. Questo lavoro sottolinea l'importanza di una sorveglianza della presenza di batteri AMR negli alimenti e di incitare lo sviluppo di strategie innovative per la mitigazione del rischio legato alla diffusione della resistenza antimicrobica negli alimenti. L'accuratezza dell'identificazione tassonomica guida le analisi successive e, per questo motivo, un metodo adeguato per identificare le specie è fondamentale. È stata studiata la riclassificazione delle specie di Enterococcus faecium clade B, utilizzando un approccio combinato di filogenomica, tipizzazione di sequenza multilocus, identità nucleotidica media e ibridazione digitale DNA-DNA. L'obiettivo è dimostrare come l'analisi del genoma sia più efficace e fornisca risultati più dettagliati riguardo alla definizione delle specie, rispetto all'analisi della sequenza del 16S rRNA. Ciò ha portato alla proposta di riclassificare tutto il clade B di E. faecium come E. lactis, riconoscendo che i due gruppi sono filogeneticamente separati, per cui è possibile definire una specifica procedura di valutazione della sicurezza, prima del loro utilizzo negli alimenti o come probiotici, compresa la considerazione per l'inclusione nella lista europea QPS. A partire da questa riclassificazione tassonomica, abbiamo sviluppato un metodo basato sulla PCR per la rapida individuazione e differenziazione di queste due specie e per discutere le principali differenze fenotipiche e genotipiche da una prospettiva clinica. A questo scopo, è stato utilizzato un allineamento del core-genoma basato sull'analisi del pangenoma. La differenza allelica tra alcuni geni del core ha permesso la progettazione di primer e l'identificazione della specie mediante PCR con una specificità del 100% e senza reattività crociata. Inoltre, i genomi clinici di E. lactis sono stati classificati come un rischio potenziale a causa della capacità di aumentare la traslocazione batterica. Gli agenti antimicrobici alternativi agli antibiotici sono una delle principali aree di sviluppo e miglioramento dell'attuale catena alimentare. Le nanoparticelle metalliche, come le nanoparticelle di platino (PtNPs), hanno suscitato interesse per le loro potenti attività catalitiche simili alle ossidasi e alle perossidasi che garantiscono forti effetti antimicrobici, e sono state proposte come potenziali candidati per superare gli inconvenienti degli antibiotici come la resistenza ai farmaci. L'obiettivo è studiare la modalità d'azione delle PtNPs in relazione alla capacità di formazione del biofilm, al meccanismo di contrasto delle specie reattive dell'ossigeno (ROS) e al quorum sensing utilizzando batteri di origine alimentare come Enterococcus faecium e Salmonella Typhimurium.Safe food and the access to it is key to sustaining life and promoting good health. Unsafe food containing harmful microorganisms or chemical substances causes more than 200 diseases, ranging from diarrhoea to cancers that particularly affect infants, young children, elderly and immunocompromised individuals. The global burden of foodborne disease affects public health, society, and economy, therefore good collaboration between governments, producers and consumers is needed to help ensure food safety and stronger food systems. The most recent survey conducted by WHO (2015) showed an estimated 600 million ill individuals and 420 000 yearly deaths associated to unsafe food. The economic impact is mainly due to the lack of safe food in low and middle income causing a US$ 110 billion is lost each year in productivity and medical expenses. The main challenges to assure food safety remain tied to our food production and supply chain, where factors like environmental contamination, consumer preferences, timely detection and surveillance of outbreaks play a crucial role. Recently, DNA-based methodologies for microbial detection and investigation have sparked special interest, mainly linked to the development of sequencing technologies. Contrary to the traditional culture-dependent methods, DNA-based techniques such as Whole Genome Sequencing (WGS) that targets fast and sensitive results at a relative low price and short processing time. Moreover, WGS confers high discriminatory power that allows to determine important genomic characteristics linked to food safety like taxonomy, pathogenic potential, virulence and antimicrobial resistance and the genetic transfer thereof. The understanding of these characteristics is fundamental to design detection and mitigation strategies to apply along the entire food-chain following a ‘One Health’ perspective, leading to gain knowledge about the microbiota that affect humans, animals, and environment. The aim of the thesis is to gain insight into the genomics of foodborne microbes for their characterization and to create or improve strategies for their detection and mitigation methods. Particularly, this thesis is focused on the assessment of the pathogenic potential based on genomic analyses including taxonomy, virulence, antibiotic resistance and mobilome studies. The second focus is to profit from the genomic insights to design rapid and time-effective detection devices and reliable mitigation methods to tackle foodborne pathogens. In more detail the following topics will be handled: The presence of multi-drug resistant strains in ready-to-eat fermented food represents a risk of public health for the spread of AMR determinants in the food chain and in the gut microbiota of consumers. Genomic analyses permitted to accurately assess the safety of E. faecium strain UC7251, with respect to its virulence and co-location of antibiotic and heavy metal resistance genes in mobile elements with conjugation capacity in different matrices. This work emphasizes the importance of a surveillance for the presence of AMR bacteria in food and to incite the development of innovative strategies for the mitigation of the risk related to antimicrobial resistance diffusion in food. The accuracy of taxonomic identification drives the subsequent analysis and, for this reason, a suitable method to identify species is crucial. The species re-classification of Enterococcus faecium clade B was investigated, using a combined approach of phylogenomics, multilocus sequence typing, average nucleotide identity and digital DNA–DNA hybridization. The goal is to show how the genome analysis is more effective and give more detailed results concerning the species definition, respect to the analysis of the 16S rRNA sequence. This led to the proposal to reclassify all the E. faecium clade B as E. lactis, recognizing the two groups are phylogenetically separate, where a specific safety assessment procedure can be designed, before their use in food or as probiotics, including the consideration for inclusion in the European QPS list. From this taxonomic re-classification, we developed a PCR-based method for rapid detection and differentiation of these two species and to discuss main phenotypic and genotypic differences from a clinical perspective. To this aim, core-genome alignment base on pangenome analysis was used. Allelic difference between certain core genes allowed primer design and species identification through PCR with 100% specificity and no cross-reactivity. Moreover, clinical E. lactis genomes categorised as a potential risk due to the ability of enhanced bacterial translocation. Antimicrobial agents alternative to antibiotics are one of the main areas of development and improvement in the current food chain. Metallic nanoparticles like Platinum nanoparticles (PtNPs), have awaken interest due to their potent catalytic activities similar to oxidases and peroxidases granting strong antimicrobial effects, have been proposed as potential candidates to overcome the drawbacks of antibiotics like drug resistance. The goal is to study the mode of action of PtNPs related to biofilm formation capacity, reactive oxygen species (ROS) coping mechanism and quorum sensing using foodborne bacteria like Enterococcus faecium and Salmonella Typhimurium

    30th European Congress on Obesity (ECO 2023)

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    This is the abstract book of 30th European Congress on Obesity (ECO 2023

    Characterising Shape Variation in the Human Right Ventricle Using Statistical Shape Analysis: Preliminary Outcomes and Potential for Predicting Hypertension in a Clinical Setting

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    Variations in the shape of the human right ventricle (RV) have previously been shown to be predictive of heart function and long term prognosis in Pulmonary Hypertension (PH), a deadly disease characterised by high blood pressure in the pulmonary arteries. The extent to which ventricular shape is also affected by non-pathological features such as sex, body mass index (BMI) and age is explored in this thesis. If fundamental differences in the shape of a structurally normal RV exist, these might also impact the success of a predictive model. This thesis evaluates the extent to which non-pathological features affect the shape of the RV and determines the best ways, in terms of procedure and analysis, to adapt the model to consistently predict PH. It also identifies areas where the statistical shape analysis procedure is robust, and considers the extent to which specific, non-pathological, characteristics impact the diagnostic potential of the statistical shape model. Finally, recommendations are made on next steps in the development of a classification procedure for PH. The dataset was composed of clinically-obtained, cardiovascular magnetic resonance images (CMR) from two independent sources; The University of Pittsburgh Medical Center and Newcastle University. Shape change is assessed using a 3D statistical shape analysis technique, which topologically maps heart meshes through an harmonic mapping approach to create a unique shape function for each shape. Proper Orthogonal Decomposition (POD) was applied to the complete set of shape functions in order to determine and rank a set of shape features (i.e. modes and corresponding coefficients from the decomposition). MRI scanning protocol produced the most significant difference in shape; a shape mode associated with detail at the RV apex and ventricular length from apex to base strongly correlated with the MRI sequence used to record each subject. Qualitatively, a protocol which skipped slices produced a shorter RV with less detail at the apex. Decomposition of sex, age and BMI also derives unique RV shape descriptors which correspond to anatomically meaningful features. The shape features are shown to be able to predict presence of PH. The predictive model can be improved by including BMI as a factor, but these improvements are mainly concentrated in identification of healthy subjects

    The investigation of metabolic profiling of human synovial fluid to provide joint disease analysis and the association with implant material wear

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    The goal of this thesis was to establish a biobank of human synovial fluid (HSF) samples. Furthermore, the methodology, conditions, fit-for-purpose criteria were needed to ensure validity and robustness. Once those conditions were met, the relationship between HSF and the behaviour of the joint implant material was to be evaluated. The current literature relating to the metabolism of osteoarthritis, synovial fluid, its storage and analysis was systematically reviewed. A biobank of HSF samples was collected. Metabolite identification of HSF was achieved using a combination of published NMR studies, the Human Metabolite Database (HMDB), 1D and 2D NMR spectra and STOCSY analysis. The stability of samples to handling, collection and long-term -80oC storage was investigated. All metabolite concentrations affected by storage were reported. This work has validated the systems and methodology to metabolically profile HSF. A variety of protein precipitation steps to maximise the metabolic information from the samples were evaluated. An acetonitrile liquid/liquid extraction performed well with additional recovery of unknown metabolites, albeit with increased variation and diminished lipid detection. To understand which metabolic components are important for mechanical wear, the metabolic profile of HSF and its wear model, BCS, were analysed for components of both fluids which correlate to measured wear in a bench-top testing rig. Wear analysis demonstrated variation in the HSF mechanical properties. This correlated to the presence of glycosaminoglycan (GAG) and proteoglycan molecules with binding to citrate and glucose. Furthermore, specific amino acids: lysine, glutamine, glycine, threonine, asparagine, proline, histidine and tyrosine, correlated with measured wear.The reported unstable metabolites must be considered for any HSF study. The acetonitrile liquid/liquid extraction method is recommended to maximise metabolite detection. The small molecule components of HSF contributing to the wear properties of implant materials has not been reported previously, is unique and opens a new field of study in implant survival.Open Acces

    Assessment of ambient assisted living systems for patients with mild cognitive impairment

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    According to the World Health Organization, about 50 million people worldwide suffer from dementia. Ten million new cases added every year. Mild Cognitive Impairment (MCI) affects more than 15% of the population aged 65. Technological solutions, such as smart home technology with ubiquitous computing devices, 24/7 telemedical observation and support can alleviate the growing problem and lower pressure on the healthcare system. This approach is also preferable for homecare patients in distant and rural areas. MCI patients are mostly home-based. Ambient Assisted Living (AAL) systems provide tools for automatic registration of vital signs and other medically and socially important information. AAL system for MCI patients is a logical answer to the problem. At the same time, many of the proposed AAL systems are proprietary, technically complicated and have a high price tag for implementation and service. Also, some proposed technical solutions not entirely reflect the opinion of healthcare stakeholders. The current study was proposed as a way to bridge the possible differences in the positions. An online anonymous questionnaire for healthcare professionals was created to prove or disprove the number of interconnected hypotheses about the necessity and feasibility of AAL system for MCI patients. The main focus was made on the hypotheses: "There is necessity of AAL systems for the healthcare" and "AAL systems are capable of providing assistance for patients with Mild Cognitive Impairment". The questionnaire was presented to more than three hundred potential respondents. Around a hundred and twenty agreed to fill it, and sixty completed the whole questionnaire. Results were analyzed to produce some directions guideline for future technical applications of AAL systems for MCI patients and future research. Descriptive statistics show support for the implementation of general AAL and variants for MCI patients. Comparative analysis of ordinal data for specific groups of respondents is done with help of non-parametric tests. Mann–Whitney–Wilcoxon test and Kruskal-Wallis test are applied. Table questions results are analyzed with chisquare for frequency tables. Group analysis demonstrated relative positive uniformity in of responses in the support of AAL of MCI patients.Segundo a Organização Mundial da Saúde, cerca de 50 milhões de pessoas em todo o mundo sofrem de demência. Dez milhões de novos casos adicionados a cada ano. O comprometimento cognitivo leve (MCI) afeta mais de 15% da população com 65 anos. Soluções tecnológicas, como tecnologia de casa inteligente com dispositivos de computação onipresentes, observação e suporte telemédico 24 horas por dia, 7 dias por semana, podem aliviar o problema crescente e diminuir a pressão sobre o sistema de saúde. Essa abordagem também é preferível para pacientes de cuidados domiciliares em áreas distantes e rurais. Os pacientes com CCL são, em sua maioria, domiciliares. Os sistemas Ambient Assisted Living (AAL) fornecem ferramentas para registro automático de sinais vitais e outras informações médicas e socialmente importantes. O sistema AAL para pacientes com MCI é uma resposta lógica para o problema. Ao mesmo tempo, muitos dos sistemas AAL propostos são proprietários, tecnicamente complicados e têm um alto preço para implementação e serviço. Além disso, algumas soluções técnicas propostas não refletem inteiramente a opinião das partes interessadas na área da saúde. O presente estudo foi proposto como forma de colmatar as possíveis diferenças nas posições. Um questionário anônimo online para profissionais de saúde foi criado para comprovar ou refutar o número de hipóteses interligadas sobre a necessidade e viabilidade do sistema AAL para pacientes com CCL. O foco principal foi feito nas hipóteses: "Há necessidade de sistemas de AAL para a saúde" e "Os sistemas de AAL são capazes de prestar assistência a pacientes com Comprometimento Cognitivo Leve". O questionário foi apresentado a mais de trezentos respondentes potenciais. Cerca de cento e vinte concordaram em preenchê-lo e sessenta preencheram todo o questionário. Os resultados foram analisados para produzir algumas diretrizes para futuras aplicações técnicas de sistemas AAL para pacientes com MCI e pesquisas futuras. Estatísticas descritivas mostram suporte para a implementação de AAL geral e variantes para pacientes com CCL. A análise comparativa de dados ordinais para grupos específicos de respondentes é feita com a ajuda de testes não paramétricos. Aplicam-se os testes de Mann-Whitney-Wilcoxon e Kruskal-Wallis. Os resultados das questões da tabela são analisados com qui-quadrado para tabelas de frequência. A análise do grupo demonstrou relativa uniformidade positiva nas respostas no suporte de AAL de pacientes com CCL.Selon l'Organisation mondiale de la santé, environ 50 millions de personnes dans le monde souffrent de démence. Dix millions de nouveaux cas ajoutés chaque année. Les troubles cognitifs légers (MCI) touchent plus de 15 % de la population âgée de 65 ans. Les solutions technologiques, telles que la technologie de la maison intelligente avec des appareils informatiques omniprésents, l'observation et le soutien télémédicaux 24 heures sur 24, 7 jours sur 7, peuvent atténuer le problème croissant et réduire la pression sur le système de santé. Cette approche est également préférable pour les patients en soins à domicile dans les régions éloignées et rurales. Les patients MCI sont pour la plupart à domicile. Les systèmes Ambient Assisted Living (AAL) fournissent des outils pour l'enregistrement automatique des signes vitaux et d'autres informations importantes sur le plan médical et social. Le système AAL pour les patients MCI est une réponse logique au problème. Dans le même temps, bon nombre des systèmes AAL proposés sont propriétaires, techniquement compliqués et ont un prix élevé pour la mise en oeuvre et le service. De plus, certaines solutions techniques proposées ne reflètent pas entièrement l'opinion des acteurs de santé. L'étude actuelle a été proposée comme un moyen de combler les différences possible dans les positions. Un questionnaire anonyme en ligne destiné aux professionnels de la santé a été créé pour prouver ou réfuter le nombre d'hypothèses interconnectées sur la nécessité et la faisabilité du système AAL pour les patients MCI. L'accent a été mis principalement sur les hypothèses: "Il existe une nécessité de systèmes AAL pour les soins de santé" et "Les systèmes AAL sont capables de fournir une assistance aux patients atteints de troubles cognitifs légers". Le questionnaire a été présenté à plus de trois cents répondants potentiels. Environ cent vingt ont accepté de le remplir, et soixante ont rempli tout le questionnaire. Les résultats ont été analysés pour produire des lignes directrices pour les futures applications techniques des systèmes AAL pour les patients MCI et l'avenir de la recherche. Les statistiques descriptives montrent un soutien à la mise en oeuvre de l'AAL général et des variantes pour les patients MCI. L'analyse comparative des données ordinales pour des groupes spécifiques de répondants est effectuée à l'aide de tests non paramétriques. Le test de Mann-Whitney-Wilcoxon et le test de Kruskal-Wallis sont appliqués. Les résultats des questions de tableau sont analysés avec le chi carré pour les tableaux de fréquence. L'analyse de groupe a démontré une uniformité positive relative dans les réponses à l'appui de l'AAL des patients MCI

    Advances in neuroproteomics for neurotrauma: unraveling insights for personalized medicine and future prospects

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    Neuroproteomics, an emerging field at the intersection of neuroscience and proteomics, has garnered significant attention in the context of neurotrauma research. Neuroproteomics involves the quantitative and qualitative analysis of nervous system components, essential for understanding the dynamic events involved in the vast areas of neuroscience, including, but not limited to, neuropsychiatric disorders, neurodegenerative disorders, mental illness, traumatic brain injury, chronic traumatic encephalopathy, and other neurodegenerative diseases. With advancements in mass spectrometry coupled with bioinformatics and systems biology, neuroproteomics has led to the development of innovative techniques such as microproteomics, single-cell proteomics, and imaging mass spectrometry, which have significantly impacted neuronal biomarker research. By analyzing the complex protein interactions and alterations that occur in the injured brain, neuroproteomics provides valuable insights into the pathophysiological mechanisms underlying neurotrauma. This review explores how such insights can be harnessed to advance personalized medicine (PM) approaches, tailoring treatments based on individual patient profiles. Additionally, we highlight the potential future prospects of neuroproteomics, such as identifying novel biomarkers and developing targeted therapies by employing artificial intelligence (AI) and machine learning (ML). By shedding light on neurotrauma’s current state and future directions, this review aims to stimulate further research and collaboration in this promising and transformative field

    Interrogating the interconnected biological networks in liver diseases reveals the core components of a perturbed homeostatic system.

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    This thesis explores the interplay between genetics, environment, and immunological regulation in metabolic associated fatty liver disease (MAFLD), metabolic steatohepatitis (MeSH), and hepatocellular carcinoma (HCC), focusing on liver response to dietary exposome and bone marrow hematopoietic stem and progenitor cells (HSPCs) activity. Using weighted gene co-expression network analysis (WGCNA), we assessed mRNA expression in murine models and human datasets, identifying conserved metabolic and immunological programs and discrepancies in immune responses. The heightened immune response in certain mouse models, reflective of bone marrow HSPCs response, is found protective and consistent with human data, emphasizing the crucial role of immune system-tumorigenesis interplay. Investigating regulatory factors, we spotlight bile acids’ significance. Maintaining a robust immune response is linked to reduced liver tumor burden, with HSPC dietary response as a potential regulatory factor. While cholesterol homeostasis disruptions alone don’t stimulate HSPCs, when combined with disrupted bile acid homeostasis, they significantly impact HSPCs. Rescuing bile acid synthesis dampens HSPC activity, underscoring bile acids' regulatory role. Our findings provide valuable insights into the intricate regulatory networks governing liver disease, presenting potential new avenues for research, including exploring bile acid metabolism’s direct regulation of bone marrow HSPCs, assessing the long-term impact of HSPC stimulation, and investigating liver cholesterol homeostasis’s effect on immunotherapy response. This research suggests exploration of minimal therapeutics targeting sensitive targets and context-driven interpretation in animal model extrapolation. Overall, our experimental approach shows potential in aiding the development of effective treatments for liver diseases, paving the way for future studies in this field
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