Explore the vast range of titles available.

Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA] − . These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy. MRI contrast agents containing the rare earth metal gadolinium are very effective, yet unstable and thus potentially hazardous. Here, the authors developed complexes between gadolinium and the scaffolding compound DOTA with increased stability, which also lend themselves to radiometal labelling.

Liver fibrosis is a common pathway shared by all forms of progressive chronic liver disease. There is an unmet clinical need for noninvasive imaging tools to diagnose and stage fibrosis, which presently relies heavily on percutaneous liver biopsy. Here, we explored the feasibility of using a novel type I collagen-targeted manganese (Mn)-based MRI probe, Mn-CBP20, for liver fibrosis imaging. In vitro characterization of Mn-CBP20 demonstrated its high binding affinity for human collagen ( K d  = 9.6 µM), high T 1 -relaxivity (48.9 mM −1  s −1 at 1.4 T and 27 °C), and kinetic inertness to Mn release under forcing conditions. We demonstrated MRI using Mn-CBP20 performs comparably to previously reported gadolinium-based type I collagen-targeted probe EP-3533 in a mouse model of carbon tetrachloride-induced liver fibrosis, and further demonstrate efficacy to detect fibrosis in a diet-induced mouse model of metabolically-associated steatohepatitis. Biodistribution studies using the Mn-CBP20 radiolabeled with the positron-emitting 52 Mn isotope demonstrate efficient clearance of Mn-CBP20 primarily via renal excretion. Mn-CBP20 represents a promising candidate that merits further evaluation and development for molecular imaging of liver fibrosis.

The design of selective metal-binding sites is a challenge in both small-molecule and macromolecular chemistry. Selective recognition of manganese (II)—the first-row transition metal ion that tends to bind with the lowest affinity to ligands, as described by the Irving-Williams series—is particularly difficult. As a result, there is a dearth of chemical biology tools with which to study manganese physiology in live cells, which would advance understanding of photosynthesis, host-pathogen interactions, and neurobiology. Here we report the rational re-engineering of the lanthanide-binding protein, lanmodulin, into genetically encoded fluorescent sensors for MnII, MnLaMP1 and MnLaMP2. These sensors with effective Kd(MnII) of 29 and 7 μM, respectively, defy the Irving-Williams series to selectively detect MnII in vitro and in vivo. We apply both sensors to visualize kinetics of bacterial labile manganese pools. Biophysical studies indicate the importance of coordinated solvent and hydrophobic interactions in the sensors’ selectivity. Our results establish lanmodulin as a versatile scaffold for design of selective protein-based biosensors and chelators for metals beyond the f-block.

Gadolinium-based contrast agents can increase the accuracy and expediency of an MRI examination. However the benefits of a contrast-enhanced scan must be carefully weighed against the well-documented risks associated with administration of exogenous contrast media. The purpose of this review is to discuss commercially available gadolinium-based contrast agents (GBCAs) in the context of pediatric radiology. We discuss the chemistry, regulatory status, safety and clinical applications, with particular emphasis on imaging of the blood vessels, heart, hepatobiliary tree and central nervous system. We also discuss non-GBCA MRI contrast agents that are less frequently used or not commercially available.

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. This 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.

BackgroundModern stent retriever-based embolectomy for patients with emergent large vessel occlusion improves outcomes. Techniques aimed at achieving higher rates of complete recanalization would benefit patients.ObjectiveTo evaluate the clinical impact of an embolectomy technique focused on continuous aspiration prior to intracranial vascular embolectomy (CAPTIVE).MethodsA retrospective review was performed of 95 consecutive patients with intracranial internal carotid artery or M1 segment middle cerebral artery occlusion treated with stent retriever-based thrombectomy over an 11-month period. Patients were divided into a conventional local aspiration group (traditional group) and those treated with a novel continuous aspiration technique (CAPTIVE group). We compared both early neurologic recovery (based on changes in National Institute of Health Stroke Scale (NIHSS) score), independence at 90 days (modified Rankin score 0–2), and angiographic results using the modified Thrombolysis in Cerebral Ischemia (TICI) scale including the TICI 2c category.ResultsThere were 56 patients in the traditional group and 39 in the CAPTIVE group. Median age and admission NIHSS scores were 78 years and 19 in the traditional group and 77 years and 19 in the CAPTIVE group. Median times from groin puncture to recanalization in the traditional and CAPTIVE groups were 31 min and 14 min, respectively (p<0.0001). While rates of TICI 2b/2c/3 recanalization were similar (81% traditional vs 100% CAPTIVE), CAPTIVE offered higher rates of TICI 2c/3 recanalization (79.5% vs 40%, p<0.001). Median discharge NIHSS score was 10 in the traditional group and 3 in the CAPTIVE group; this difference was significant. There was also an increased independence at 90 days (25% traditional vs 49% CAPTIVE).ConclusionsThe CAPTIVE embolectomy technique may result in higher recanalization rates and better clinical outcomes.

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.

A G4C2 hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed in regions of neurodegeneration. The accumulation of repetitive RNAs and dipeptide repeat protein (DPR) are two proposed mechanisms of toxicity in C9-ALS/FTLD and linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport is regulated by the phenylalanine-glycine nucleoporins (FG nups) that comprise the nuclear pore complex (NPC) permeability barrier. However, the relationship between FG nups and TDP-43 pathology remains elusive. Our studies show that nuclear depletion and cytoplasmic mislocalization of one FG nup, NUP62, is linked to TDP-43 mislocalization in C9-ALS/FTLD iPSC neurons. Poly-glycine arginine (GR) DPR accumulation initiates the formation of cytoplasmic RNA granules that recruit NUP62 and TDP-43. Cytoplasmic NUP62 and TDP-43 interactions promotes their insolubility and NUP62:TDP-43 inclusions are frequently found in C9orf72 ALS/FTLD as well as sporadic ALS/FTLD postmortem CNS tissue. Our findings indicate NUP62 cytoplasmic mislocalization contributes to TDP-43 proteinopathy in ALS/FTLD. ALS and FTLD are both characterized by insoluble cytoplasmic depositions of TDP43. Here the authors show that the nucleopore protein NUP62 is mislocalized in C9orf72 and sporadic ALS/FTLD and propose that it interacts with TDP-43 to promote its insolubility.