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Overcoming multidrug resistance has always been a major challenge in cancer treatment. Recent evidence suggested epithelial-mesenchymal transition plays a role in MDR, but the mechanism behind this link remains unclear. We found that the expression of multiple ABC transporters was elevated in concordance with an increased drug efflux in cancer cells during EMT. The metastasis-related angiopoietin-like 4 (ANGPTL4) elevates cellular ATP to transcriptionally upregulate ABC transporters expression via the Myc and NF-κB signaling pathways. ANGPTL4 deficiency reduced IC 50 of anti-tumor drugs and enhanced apoptosis of cancer cells. In vivo suppression of ANGPTL4 led to higher accumulation of cisplatin-DNA adducts in primary and metastasized tumors, and a reduced metastatic tumor load. ANGPTL4 empowered cancer cells metabolic flexibility during EMT, securing ample cellular energy that fuels multiple ABC transporters to confer EMT-mediated chemoresistance. It suggests that metabolic strategies aimed at suppressing ABC transporters along with energy deprivation of EMT cancer cells may overcome drug resistance.

Background: Endoscopic assessment for the diagnosis of gastric cancer is limited by interoperator variability and lack of real-time capability. Recently, Raman spectroscopy-based artificial intelligence (AI) has been proposed as a solution to overcome these limitations. Objective: To compare the performance of the AI-enabled Raman spectroscopy with that of high-definition white light endoscopy (HD-WLE) for the risk classification of gastric lesions. Methods: This was a randomized double-arm feasibility proof-of-concept trial in which participants with suspected gastric neoplasia underwent endoscopic assessment using either the Raman spectroscopy-based AI (SPECTRA IMDx™) or HD-WLE performed by expert endoscopists. Identified lesions were classified in real time as having either low or high risk for neoplasia. Diagnostic outcomes were compared between the two groups using histopathology as the reference. Results: A total of 20 patients with 25 lesions were included in the study. SPECTRA, in real-time, performed at a statistically similar level to that of HD-WLE performed by expert endoscopists, achieving an overall sensitivity, specificity, and accuracy of 100%, 80%, and 89.0%, respectively, by patient; and 100%, 80%, and 92%, respectively, by lesion, while expert endoscopists using HD-WLE attained a sensitivity, specificity, and accuracy of 100%, 80%, and 90%, respectively, by patient; and 100%, 83.3%, and 91.7%, respectively, by lesion, in differentiating high-risk from low-risk gastric lesions. Conclusions: The SPECTRA’s comparable performance with that of HD-WLE suggests that it can potentially be a valuable adjunct for less experienced endoscopists to attain accurate and real-time diagnoses of gastric lesions. Larger-scale prospective randomized trials are recommended to validate these promising results further.

Through extensive multisystem phenotyping, the central aim of Project PICMAN is to correlate metabolic flexibility to measures of cardiometabolic health, including myocardial diastolic dysfunction, coronary and cerebral atherosclerosis, body fat distribution and severity of non-alcoholic fatty liver disease. This cohort will form the basis of larger interventional trials targeting metabolic inflexibility in the prevention of cardiovascular disease. Participants aged 21–72 years with no prior manifest atherosclerotic cardiovascular disease (ASCVD) are being recruited from a preventive cardiology clinic and an existing cohort of non-alcoholic fatty liver disease (NAFLD) in an academic medical centre. A total of 120 patients will be recruited in the pilot phase of this study and followed up for 5 years. Those with 10-year ASCVD risk ≥ 5% as per the QRISK3 calculator are eligible. Those with established diabetes mellitus are excluded. Participants recruited undergo a detailed assessment of health behaviours and physical measurements. Participants also undergo a series of multimodality clinical phenotyping comprising cardiac tests, vascular assessments, metabolic tests, liver and neurovascular testing. Blood samples are also being collected and banked for plasma biomarkers, ‘multi-omics analyses’ and for generation of induced pluripotent stem cells (iPSC). Extensive evidence points to metabolic dysregulation as an early precursor of cardiovascular disease, particularly in Asia. We hypothesise that quantifiable metabolic inflexibility may be representative of an individual in his/her silent, but high-risk progression towards insulin resistance, diabetes and cardiovascular disease. The platform for interdisciplinary cardiovascular-metabolic-neurovascular diseases (PICMAN) is a pilot, prospective, multi-ethnic cohort study.