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Anthropomorphic AI traits and roles in customer journeys: a systematic review and the interaction–activation–outcome framework
Full text linkInvestigating the effect of chemotherapy on heterogeneity and plasticity of colorectal cancer liver metastases
No full textChemotherapy is the most common treatment for colorectal cancer liver metastases (CRC LMs), which can significantly prolong patient survival. However, limited chemotherapy response and high rates of disease recurrence are common challenges contributing to poor patient outcome. A better understanding of how chemotherapy impacts specific cell types and states in LMs could aid development of improved therapeutic strategies for metastatic CRC. In this thesis, I aimed to characterise how chemotherapy alters the transcriptional and spatial landscape of cancer and tumour microenvironment cells in CRC LMs. Firstly, I analysed single-cell RNA-sequencing data from 87 CRC LM patients to annotate fine-grained cancer and tumour microenvironment cell subsets, characterising cellular heterogeneity across all major cellular compartments. Comparing transcriptional profiles and abundance of detailed subsets between chemotherapy-treated and untreated LMs revealed significant differences related to treatment. In treated LMs, greater abundance of dendritic cells and inflammatory macrophages, alongside increased expression of TNF-α signalling via NF-κB across multiple cell types, suggested an enhanced inflammatory response. Treated LMs also displayed reduced abundance of exhausted CD8 T cells and pro-tumoural SPP1+ macrophages suggesting that chemotherapy may alleviate immunosuppression. Comparisons based on responsiveness to chemotherapy elucidated that certain cancer cell states in better responding patients upregulated regenerative/fetal, apoptotic and inflammatory pathway signatures, and downregulated proliferation genes, compared to worse responders and untreated LMs. Therefore, the retention of cancer cells in a slower-cycling, regenerative state may relate to favourable chemotherapy outcome. Subsequent spatial mapping of fine-grained cell types using Visium spatial transcriptomics data of treated and untreated LMs supported differences in transcriptional pathways identified in single-cell data. Finally, bulk RNA-sequencing of CRC LM patient-derived organoids revealed that 5-fluorouracil, SN-38 and oxaliplatin chemotherapies induced inflammatory and regenerative signatures as an early response to treatment. Profiling recovery of patient-derived organoids after 5-fluorouracil treatment suggested transitions towards alternative non-canonical states that may relate to worse response to therapy. Overall, our results supported chemotherapy-induced alterations across cancer and tumour microenvironment cells in CRC LMs, which was dependent on patient response to chemotherapy. Our findings provide insights into the wide-ranging effects of chemotherapy at single-cell resolution that could inform identification of therapeutic targets
wgbstools: A computational suite for DNA methylation sequencing data representation, visualization, and analysis
No full textImproving the management and outcomes of preschool wheeze: protocol of a prospective multicentre cohort study.
Full text linkINTRODUCTION: Preschool wheeze and asthma are associated with substantial morbidity and impaired future lung function. Yet, wheeze is unreliably reported with high disagreement (>50%) between parental and physician observations. Objectively defining wheeze and its reversibility could enable an earlier asthma diagnosis and improve preschool wheeze management.Our primary aim is to determine in preschool children (aged 0.5-6 years) suspected of asthma whether adding WheezeScan to routine clinical assessment (vs assessment without WheezeScan) improves the diagnosis of asthma. Our primary hypothesis is that using WheezeScan in preschool children suspected of asthma is associated with increased definitive asthma diagnoses in this age group. Our secondary aims are to (a) examine the effect of using WheezeScan on patient-reported outcomes (PROs) and (b) healthcare costs. Our secondary hypothesis is that using WheezeScan in preschool children suspected of asthma is associated with improved quality of life without incurring additional healthcare costs. METHODS AND ANALYSIS: Our multicentre prospective cohort study involves recruiting 102 preschool children suspected of asthma. WheezeScan, a user-friendly digital device, incorporates artificial intelligence to objectively define wheeze and its response to bronchodilators. Over 6 weeks, parents/caregivers use the WheezeScan two times per day and whenever wheezing is suspected. If wheeze is detected, an inhaled short-acting β2-agonist is administered and WheezeScan determines if wheeze resolves thereafter.Our primary endpoint is the proportion of children with a definitive asthma diagnosis, compared with baseline, based on the treating clinician's assessment using WheezeScan data. Our secondary outcomes are PROs, reflecting generic health-related quality-of-life and cough-specific (if chronic cough present) outcomes and health costs. ETHICS AND DISSEMINATION: The Children's Health Queensland Human Research Ethics Committee (HREC/23/QCHQ/100691) and the Queensland University of Technology Office of Research Ethics and Integrity approved the study. We will publish and share results with the academic and healthcare communities and relevant patient organisations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12623000904673
Counting cells can accurately predict small-molecule bioactivity benchmarks.
Full text linkAccurately predicting the activity of a chemical in each bioactivity assay based on its already known properties is extremely useful in drug development. Unfortunately, we discovered that many assays in widely used assay-activity benchmark datasets directly relate to cell health and cytotoxicity. Many other assays intend to capture a more specific phenotype, but their active compounds impact cell count, while inactives do not. In both cases, counting cells achieves unexpectedly high performance in these benchmarks, making them less useful for discerning whether additional properties, such as phenotypic profiles (mRNA or Cell Painting), provide additional useful information on bioactivity. To accomplish this goal, we recommend filtering benchmarks to exclude such assays and including a cell-count baseline. Using a benchmark with 24 protein-target assays, we confirm that models leveraging Cell Painting image-based profiles outperformed the baseline cell count model. We propose several other practical recommendations for benchmarking machine learning models for predicting bioactivity and assessing the added value of mRNA, protein, or image-based profiles
Building capacity for delivery of youth-targeted mental health interventions in Vietnam and Cambodia: Protocol for a cluster-randomised controlled feasibility trial (Preprint)
No full textEsophageal Mucosal Mast Cell Density and Degranulation are Increased in Gastro-esophageal Reflux Disease.
No full textIntroduction: Gastro-esophageal reflux disease (GERD) is a chronic condition encompassing visceral pain - experienced as heartburn and, in some cases, inflammation of the esophageal mucosa. Although mast cell dysregulation has been described in disorders of gut-brain interaction, it has been understudied in GERD. We aimed to characterize mast cell localization and degranulation in GERD esophageal mucosa. Methods: Distal esophageal biopsies were collected from healthy control (HC; N=10), functional heartburn (FH; N=9), non-erosive reflux disease (NERD; N=13), and erosive reflux disease (ERD; N=12) subjects. Immunohistochemistry was used to visualize tryptase expression in the esophageal mucosa. The localization of tryptase+ mast cells were identified as intraepithelial or papillary, and the degranulation state of individual mast cells was determined based on tryptase staining pattern. Results: There was an increased density of mast cells in the esophageal papillae and epithelium of ERD patients compared to HCs. The density of degranulated intraepithelial mast cells was significantly higher in FH and ERD subjects compared to HCs, with a trend towards increase in NERD. In NERD and ERD, the density of degranulated mast cells in papillae was significantly higher than HCs. In FH, density of intraepithelial mast cells positively correlated with RDQ score. Conclusions: Mast cells are more numerous in the esophageal mucosa of ERD subjects, and activity is increased in FH, NERD, and ERD subjects. This could contribute to mucosal inflammation, barrier dysfunction, and visceral hypersensitivity in GERD patients. Future studies should investigate the role of mucosal mast cells in GERD, representing a possible future treatment target
Modelled impact of a multi-cancer early detection screening programme on the demand for diagnostics in England.
Full text linkBACKGROUND: People with a cancer signal detected via multi-cancer early detection (MCED) screening need timely access to confirmatory diagnostic testing. We estimated the likely change in demand for diagnostic testing in England if MCED screening were introduced. METHODS: Diagnostic demand was modelled based on (1) estimates of the volume of people aged 50-79 years who would be referred for diagnostic investigation following a 'cancer signal detected' result after MCED screening and (2) MCED test performance metrics. Predicted usage was compared with current annual usage using routine NHS datasets. RESULTS: In an established MCED screening programme, assuming 70% of the total eligible population is screened annually (~13 million), the relative change in diagnostic demand was greatest for colonoscopy (+2.09%; +13,730 each year); the greatest absolute change was for computed tomography (CT; +0.76%; +62,320). This equates to +1040 colonoscopies and +4720 CT scans for every million screened. CONCLUSIONS: The predicted relative increase in diagnostic testing generated by MCED screening is small, though a large eligible population and maximum uptake could translate into a large number of procedures. Cancer diagnoses brought forward in time through screening should reduce diagnostic use for symptomatic presentations in the future
