ObjectivesPancreatic cancer (PCa) is treatable by surgery when detected at an early stage. Non-invasive imaging methods able to detect both established tumours and their precursor lesions are needed to select patients for surgery. We investigated here whether pancreatic preneoplasia could be detected prior to the development of invasive cancers in genetically engineered mouse models of PCa using metabolic imaging.DesignThe concentrations of alanine and lactate and the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were measured in extracts prepared from the pancreas of animals at different stages of disease progression; from pancreatitis, through tissue with predominantly low-grade and then high-grade pancreatic intraepithelial neoplasia and then tumour. 13C magnetic resonance spectroscopic imaging (13C-MRSI) was used to measure non-invasively changes in 13C labelling of alanine and lactate with disease progression, following injection of hyperpolarised [1-13C]pyruvate.ResultsProgressive decreases in the alanine/lactate concentration ratio and ALT/LDH activity ratio with disease progression were accompanied by a corresponding decrease in the [1-13C]alanine/[1-13C]lactate signal ratio observed in 13C-MRSI images of the pancreas.ConclusionsMetabolic imaging with hyperpolarised [1-13C]pyruvate enables detection and monitoring of the progression of PCa precursor lesions. Translation of this MRI technique to the clinic has the potential to improve the management of patients at high risk of developing PCa.

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Subduction zones have recurrently formed on Earth. Previous studies have, however, suggested that they are unlikely to start in the interior of a pristine ocean. Instead, they seem to be more likely to form from another pre-existing subduction zone. One widely cited conceptual model to start new subduction zones is polarity reversal, resulting from the shutdown of a pre-existent subduction zone due to the arrival of a buoyant block at the trench. However, the dynamic conditions by which this process occurs remain elusive. Here, we present 3D numerical models of subduction zone initiation by polarity reversal resulting from the arrival of an oceanic plateau at the trench. Our results show that this process is more likely to occur for old subducting plates and narrow plateaus, and that new subduction zones can form from previous ones in a self-replicating manner, without requiring any other external tectonic forcing.

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Subduction provides the primary driving force for plate tectonics. However, the mechanisms leading to the formation of new subduction zones remain debated. An example is the Lesser Antilles Arc in the Atlantic. Previous initiation mechanisms have implied the transmission of subduction from the Pacific Ocean or the impact of a plume head. Here, we use geodynamic models to simulate the evolution of the Caribbean region during the Cretaceous, where the eastern Pacific subduction triggered the formation of a new subduction zone in the Atlantic. The simulations show how the collision of the old Caribbean plateau with the Central America margin lead to the formation of a new Atlantic subduction zone by polarity reversal. The results further show how subduction renewal on the back of the old Caribbean plateau (present-day Central America) resulted in a major mantle flow reorganization that generated a subduction-induced plume consistent with the formation of the Caribbean Large Igneous Province.

Background Antibodies revolutionized cancer treatment over the past decades. Despite their successfully application, there are still challenges to overcome to improve efficacy, such as the heterogeneous distribution of antibodies within tumors. Tumor microenvironment features, such as the distribution of tumor and other cell types and the composition of the extracellular matrix may work together to hinder antibodies from reaching the target tumor cells. To understand these interactions, we propose a framework combining in vitro and in silico models. We took advantage of in vitro cancer models previously developed by our group, consisting of tumor cells and fibroblasts co-cultured in 3D within alginate capsules, for reconstruction of tumor microenvironment features. Results In this work, an experimental-computational framework of antibody transport within alginate capsules was established, assuming a purely diffusive transport, combined with an exponential saturation effect that mimics the saturation of binding sites on the cell surface. Our tumor microenvironment in vitro models were challenged with a fluorescent antibody and its transport recorded using light sheet fluorescence microscopy. Diffusion and saturation parameters of the computational model were adjusted to reproduce the experimental antibody distribution, with root mean square error under 5%. This computational framework is flexible and can simulate different random distributions of tumor microenvironment elements (fibroblasts, cancer cells and collagen fibers) within the capsule. The random distribution algorithm can be tuned to follow the general patterns observed in the experimental models. Conclusions We present a computational and microscopy framework to track and simulate antibody transport within the tumor microenvironment that complements the previously established in vitro models platform. This framework paves the way to the development of a valuable tool to study the influence of different components of the tumor microenvironment on antibody transport.

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