DOTA-Based Plectin-1 Targeted Contrast Agent Enables Detection of Pancreatic Cancer in Human Tissue.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy with extremely poor patient survival rates. A key reason for the poor prognosis is the lack of effective diagnostic tools to detect the disease at curable, premetastatic stages. Tumor surgical resection is PDAC's first-line treatment, however distinguishing between cancerous and healthy tissue with current imaging tools remains a challenge. In this work, we report a DOTA-based fluorescent probe targeting plectin-1 for imaging PDAC with high specificity. To enable heterogeneous functionalization of the DOTA-core with multiple targeting peptide units and the fluorophore, a novel, fully clickable synthetic route that proceeds in one pot was developed. Extensive validation of the probe set the stage for PDAC detection in mice and human tissue. Altogether, these findings may pave the way for improved clinical understanding and early detection of PDAC progression as well as more accurate resection criteria.

Does size matter? - Comparing pyranoses with septanoses as ligands of the bacterial lectin FimH.

The pharmacological modulation of disease-relevant carbohydrate-protein interactions represents an underexplored area of medicinal chemistry. One particular challenge in the design of glycomimetic compounds is the inherent instability of the glycosidic bond toward enzymatic cleavage. This problem has traditionally been approached by employing S-, N-, or C-glycosides with reduced susceptibility toward glycosidases. The application of ring-extended glycomimetics is an innovative approach to circumvent this issue. On the example of the bacterial adhesin FimH, it was explored how design principles from pyranose glycomimetics transfer to analogous septanose structures. A series of ring-extended FimH antagonists exhibiting the well-proven pharmacophore necessary for targeting the tyrosine-gate of FimH was synthesized. The resulting septanoses were evaluated for their affinity to the conformationally rigid isolated lectin domain of FimH (FimHLD), as well as a structurally flexible full-length FimH (FimHFL) construct. Some elements of potent mannoside-based FimH antagonists could be successfully transferred to septanose-based ligands, ultimately resulting in a 32-fold increase in binding affinity. Interestingly, the canonical ca. 100-fold loss of binding affinity between FimHLD and FimHFL is partly mitigated by the more flexible septanose antagonists, hinting at potentially differing interaction features of the flexible glycomimetics with intermediately populated states during the conformational transition of FimHFL.

An alternative soft tissue analysis following mandibular setback by sagittal split ramus osteotomy.

OBJECTIVE: The objective of this study was to determine alternative ratios of soft-to-hard tissue movement after mandibular setback, taking skeletal relapse and differing patterns of facial divergence into account. STUDY DESIGN: Thirty patients were analyzed cephalometrically over a mean follow-up period of 14 months. RESULTS: The relationship between skeletal and soft tissue movements in the mentolabial folds and at the pogonion was 1:1. Final skeletal relapse was 0.8 mm at the B-point and 0.5 mm at the pogonion. Hence, the alternative ratios were 81% and 68%, respectively. The alternative ratio for the mentolabial sulcus was considerably lower in the low- than in the high- and medium-angle groups of patients. However, there was no statistically significant difference between the patient groups with different facial patterns. CONCLUSION: When the smallness of the measured relapse and the tracing error are taken into account, the difference between the alternative and the conventional ratios was insignificant.