Repurposing sodium stibogluconate as an uracil DNA glycosylase inhibitor against prostate cancer using a time-resolved oligonucleotide-based drug screening platform.

Repurposing drugs can significantly reduce the time and costs associated with drug discovery and development. However, many drug compounds possess intrinsic fluorescence, resulting in aberrations such as auto-fluorescence, scattering and quenching, in fluorescent high-throughput screening assays. To overcome these drawbacks, time-resolved technologies have received increasing attention. In this study, we have developed a rapid and efficient screening platform based on time-resolved emission spectroscopy in order to screen for inhibitors of the DNA repair enzyme, uracil-DNA glycosylase (UDG). From a database of 1456 FDA/EMA-approved drugs, sodium stibogluconate was discovered as a potent UDG inhibitor. This compound showed synergistic cytotoxicity against 5-fluorouracil-resistant cancer cells. This work provides a promising future for time-resolved technologies for high-throughput screening (HTS), allowing for the swift identification of bioactive compounds from previously overlooked scaffolds due to their inherent fluorescence properties.

Covalent inhibition of epidermal growth factor receptor using a long-lived iridium(III)-afatinib probe.

The overexpression and overactivation of epidermal growth factor receptor (EGFR) are frequently observed in human cancers, including squamous cell carcinoma and adenocarcinoma. In this study, a covalent EGFR probe was developed by conjugating afatinib to an iridium(III) scaffold. Complex 1 showed enhanced luminescence in living epidermoid squamous carcinoma A431 cells compared to other cell lines, via engaging EGFR as confirmed via CETSA and knockdown experiments. Moreover, complex 1 inhibited downstream targets of EGFR in cellulo with repression persisting after removal of the complex, indicating an irreversible mode of inhibition. Finally, complex 1 showed potent antiproliferative activity against A431 cells with comparable potency to afatinib alone. To our knowledge, complex 1 is the first EGFR covalent inhibitor based on an iridium scaffold reported in the literature, with the potential to be further explored as a theranostic agent in the future.

[CT imaging features and misdiagnosis analysis of occult anterior calcaneal process fracture].

OBJECTIVE: To explore CT imaging features and reason for missed diagnosis of clinical practice of occult anterior calcaneal process fracture. METHODS: From July 2013 to November 2018, the clinical data of 13 patients with occult an anterior calcaneal process fracture were retrospectively analyzed, including 2 males and 11 females, aged from 22 to 54 years old. Classification of fracture, displacement of fracture, direction of fracture line, size of fracture, with or without tarsal coalition, other fractures and misdiagnosis, the time from injury to diagnosis, condition of treatment and fracture healing were observed according to case history, data of X-ray and CT. RESULTS: Thirteen patients were diagnosed as occult anterior calcaneal process fracture after CT examination. According to Degan classification, 9 patients were type I, 4 patients were typeII; 4 patients were occurred displacement, and 9 patients did not occurred displacement. On the horizontally CT, fracture line of 12 patients showed transverse, 1 patient oblique, and the size of fracture ranged from 0.40 to 1.72 cm; while on the sagittal view, fracture line of 12 patients showed vertical, 1 patient oblique, and the size of fracture ranged from 0.10 to 0.59 cm. No patients combined with talocalcaneal and scaphoid bridge. Six patients were simple anterior calcaneal process fracture, 7 patients combined with other fractures. Eight patients were misdiagnosed. The time from injury to diagnose ranged from 0 to 21 days. Nine patients with type Iwere performed conservative treatment, 6 patients healed well and 3 patients with fracture line less than 1 cm on horizontally view occurred fracture nonunion. Four patients with type II did not perform operation, and fracture were not union, regardless of fracture size. CONCLUSIONS: Occult anterior calcaneal process fracture have high rate of missed diagnosis in clinical practice. CT imaging features of fracture showed that most fracture line were transverse on CT horizontal plane while vertical on CT sagittal plane, as well as small side of fragment on CT sagittal plane with differernt sizes of fragment on CT horizontal plane; type Ifracture with fragment less than 1 cm on CT horizontal plane and type II both have high rate of nonunion while treated with conservative treatment.