Concurrent targeting of GSK3 and MEK as a therapeutic strategy to treat pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. However, drug discovery for PDAC treatment has proven complicated, leading to stagnant therapeutic outcomes. Here, we identify Glycogen synthase kinase 3 (GSK3) as a therapeutic target through a whole-body genetic screening utilizing a '4-hit' Drosophila model mimicking the PDAC genotype. Reducing the gene dosage of GSK3 in a whole-body manner or knocking down GSK3 specifically in transformed cells suppressed 4-hit fly lethality, similar to Mitogen-activated protein kinase kinase (MEK), the therapeutic target in PDAC we have recently reported. Consistently, a combination of the GSK3 inhibitor CHIR99021 and the MEK inhibitor trametinib suppressed the phosphorylation of Polo-like kinase 1 (PLK1) as well as the growth of orthotopic human PDAC xenografts in mice. Additionally, reducing PLK1 genetically in 4-hit flies rescued their lethality. Our results reveal a therapeutic vulnerability in PDAC that offers a treatment opportunity for patients by inhibiting multiple targets.

Habitat suitability maps for juvenile tri-spine horseshoe crabs in Japanese intertidal zones: A model approach using unmanned aerial vehicles and the Structure from Motion technique.

The tri-spine horseshoe crab, Tachypleus tridentatus, is a threatened species that inhabits coastal areas from South to East Asia. A Conservation management system is urgently required for managing its nursery habitats, i.e., intertidal flats, especially in Japan. Habitat suitability maps are useful in drafting conservation plans; however, they have rarely been prepared for juvenile T. tridentatus. In this study, we examined the possibility of constructing robust habitat suitability models (HSMs) for juveniles based on topographical data acquired using unmanned aerial vehicles and the Structure from Motion (UAV-SfM) technique. The distribution data of the juveniles in the Tsuyazaki and Imazu intertidal flats from 2017 to 2019 were determined. The data were divided into a training dataset for HSM construction and three test datasets for model evaluation. High accuracy digital surface models were built for each region using the UAV-SfM technique. Normalized elevation was assessed by converting the topographical models that consider the tidal range in each region, and the slope was calculated based on these models. Using the training data, HSMs of the juveniles were constructed with normalized elevation and slope as the predictor variables. The HSMs were evaluated using the test data. The results showed that HSMs exhibited acceptable discrimination performance for each region. Habitat suitability maps were built for the juveniles in each region, and the suitable areas were estimated to be approximately 6.1 ha of the total 19.5 ha in Tuyazaki, and 3.7 ha of the total 7.9 ha area in Imazu. In conclusion, our findings support the usefulness of the UAV-SfM technique in constructing HSMs for juvenile T. tridentatus. The monitoring of suitable habitat areas for the juveniles using the UAV-SfM technique is expected to reduce survey costs, as it can be conducted with fewer investigators over vast intertidal zones within a short period of time.