Ramsay, I. | bioRxiv Science

bioRxiv2024

Molecular Magnetic Resonance Imaging of Dysregulated Zinc Secretion Detects Early Pancreatic Ductal Adenocarcinoma Lesions and Response to KRASG12D Inhibitor Treatment

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, primarily due to late-stage diagnosis and limited treatment options. Zinc homeostasis is markedly dysregulated in PDAC and this dysregulation can be probed by administering a secretagogue to stimulate zinc secretion (SSZS) in the exocrine pancreas and imaging this secretion with a zinc sensitive MRI probe. This study demonstrates the potential of SSZS MRI for early detection, monitoring treatment response, and assessing recurrence after treatment withdrawal in PDAC. Our approach relies on interrogating the pancreas, circumventing the challenge of locating small, elusive tumors. By SSZS MRI, we detected PDAC by observing the unique zinc hypersecretory activity of the pancreas when malignancy is present. We observed dysregulation of zinc transporters in both human and mouse pancreas containing PDAC and confirmed secretagogue-stimulated zinc secretion in vitro and in vivo. We found that combining secretagogues such as secretin and caerulein maximized zinc secretion and as such MRI signal in the pancreas. Notably, SSZS MRI detected treatment responses to KRAS G12D inhibition within 3-5 days and identified cancer recurrence as early as one day post-treatment withdrawal. Additionally, secretagogue stimulation improved treatment responses and delayed recurrence in both treatment models. These findings suggest that SSZS MRI could significantly enhance PDAC diagnosis and management, providing a novel, non-invasive imaging modality to improve patient outcomes. STATEMENT OF SIGNIFICANCEThis study demonstrates the utility of secretagogue-stimulated zinc secretion (SSZS) MRI in detecting pancreatic ductal adenocarcinoma (PDAC) at early stages, monitoring treatment responses, and assessing cancer recurrence, thereby offering a promising non-invasive imaging modality to improve PDAC patient management and outcomes.

cancer biology↗

bioRxiv2023

Connectome architecture shapes large-scale cortical reorganization in schizophrenia: a worldwide ENIGMA study

While schizophrenia is considered a prototypical network disorder characterized by widespread brain-morphological alterations, it still remains unclear whether distributed structural alterations robustly reflect underlying network layout. Here, we tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n=207), we evaluated structural alterations of schizophrenia against two network susceptibility models: i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; ii) epicenter mapping, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Schizophrenia-related structural alterations co-localized with interconnected functional and structural hubs and harbored temporo-paralimbic and frontal epicenters. Findings were robust across sites and related to individual symptom profiles. We observed localized unique epicenters for first-episode psychosis and early stages, and transmodal epicenters that were shared across first-episode to chronic stages. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, yielding insights in pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work contributes to recognizing potentially common pathways to better understand macroscale structural alterations, and inter-individual variability in schizophrenia.

neuroscience↗