A Comparative Analysis of Orthotopic and Subcutaneous Pancreatic Tumour Models: Tumour Microenvironment and Drug Delivery

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour models are needed to test potential treatments. This paper compared orthotopic and subcutaneous PDAC tumour models and their suitability for drug delivery studies. A novel aspect was the broad range of tumour properties that were studied, including tumour growth, histopathology, functional vasculature, perfusion, immune cell infiltration, biomechanical characteristics, and especially the extensive analysis of the structure and the orientation of the collagen fibres in the two tumour models. The study unveiled new insights into how these factors impact the uptake of a fluorescent model drug, the macromolecule called 800CW. While the orthotopic model offered a more clinically relevant microenvironment, the subcutaneous model offered advantages for drug delivery studies, primarily due to its reproducibility, and it was characterised by a more efficient drug uptake facilitated by its collagen organisation and well-perfused vasculature. The tumour uptake seemed to be influenced mainly by the structural organisation and the alignment of the collagen fibres and perfusion. Recognising the diverse characteristics of these models and their multifaceted impacts on drug delivery is crucial for designing clinically relevant experiments and improving our understanding of pancreatic cancer biology

Effect of high-intensity interval training on fitness, fat mass and cardiometabolic biomarkers in children with obesity: a randomised controlled trial

Background: Paediatric obesity significantly increases the risk of developing cardiometabolic diseases across the lifespan. Increasing cardiorespiratory fitness (CRF) could mitigate this risk. High-intensity interval training (HIIT) improves CRF in clinical adult populations but the evidence in paediatric obesity is inconsistent. Objectives: The objectives of this study were to determine the efficacy of a 12-week, HIIT intervention for increasing CRF and reducing adiposity in children with obesity. Methods: Children with obesity (n = 99, 7–16 years old) were randomised into a 12-week intervention as follows: (1) HIIT [n = 33, 4 × 4-min bouts at 85–95% maximum heart rate (HR), interspersed with 3 min of active recovery at 50–70% HR, 3 times/week] and nutrition advice; (2) moderate-intensity continuous training (MICT) [n = 32, 44 min at 60–70% HR, 3 times/week] and nutrition advice; and (3) nutrition advice only (nutrition) [n = 34]. CRF was quantified through a maximal exercise test ((Formula presented.)) while adiposity was assessed using magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry (DXA) and air-displacement plethysmography. Results: HIIT stimulated significant increases in relative (Formula presented.) compared with MICT (+3.6 mL/kg/min, 95% CI 1.1–6.0, P = 0.004) and the nutrition intervention (+5.4 mL/kg/min, 95% CI 2.9–7.9, P = 0.001). However, the intervention had no significant effect on visceral and subcutaneous adipose tissue, whole body composition or cardiometabolic biomarkers (P > 0.05). Conclusion: A 12-week, HIIT intervention was highly effective in increasing cardiorespiratory fitness when compared with MICT and nutrition interventions. While there were no concomitant reductions in adiposity or blood biomarkers, the cardiometabolic health benefit conferred through increased CRF should be noted. Clinical trials registration number: Clinicaltrials.gov; NCT01991106