A Multidisciplinary Approach to Hip Fractures: Evaluating Outcomes on Mortality and Secondary Hip Fractures.

Fracture liaison services (FLS) have been introduced in Japan and several other countries to reduce medical complications and secondary fractures. We aimed to evaluate the effects of the implementation of an FLS approach on patient outcomes during hospitalization at our hospital and over a 2-year follow-up post-injury. This retrospective cohort study included patients ≥ 60 years admitted to our hospital for hip fragility fractures between October 1, 2016, and July 31, 2020. Patient groups were defined as those treated before (control group, n=238) and after (FLS group, n=196) establishment of the FLS protocol at our institution. The two groups were compared in terms of time to surgery, length of hospital stay, and the incidence of complications after admission, including secondary hip fracture and mortality rates. The follow-up period was 24 months. FLS focuses on early surgery within 48 h of injury and assessing osteoporosis treatment before injury to guide post-discharge anti-osteoporosis medication. FLS reduced the length of hospital stay (p<0.001) and the prevalence of complications after admission (p<0.001), particularly cardiovascular disease, and it increased adherence to anti-osteoporosis medication. These FLS effects resulted in lower secondary hip fracture and mortality rates at 12 and 24 months post-injury. FLS for fragility hip fractures can improve patient outcomes during hospitalization and over a 2-year follow-up period.

Radiation responsive PROTAC nanoparticles for tumor-specific proteolysis enhanced radiotherapy.

Proteolysis targeting chimeras (PROTACs) is a promising strategy for cancer therapy. However, the always-on bioactivity of PROTACs may lead to non-target toxicity, which restricts their antitumor performance. Here, we developed an X-ray radiation responsive PROTAC nanomicelle (RCNprotac) by covalently conjugating a reported small molecule PROTAC (MZ1) to hydrophilic PEG via a diselenide bond-containing carbon chain, which then self-assembled into a 141.80 ± 5.66 nm nanomicelle. The RCNprotac displayed no bioactivity during circulation due to the occupation of the hydroxyl group on the E3 ubiquitin ligand component and could effectively accumulate at the tumor site owing to the enhanced permeability and retention effect. Upon exposure to X-ray radiation, the radiation-sensitive diselenide bonds were broken to specifically release MZ1 for tumor BRD4 protein degradation. Furthermore, the reduction in the BRD4 protein level could increase the tumor's sensitivity to radiation. RCNprotac showed a synergistic enhancement of antitumor effects both in vitro and in vivo. We believe that this X-ray-responsive PROTAC nanomicelle could provide a new strategy for the X-ray-activated spatiotemporally controlled protein degradation and for the BRD4 proteolysis enhanced tumor radiosensitivity.

Role of the thiosugar ring in the inhibitory activity of salacinol, a potent natural α-glucosidase inhibitor.

Herein, ring-cleaved (24) and truncated (25) analogues of an azasugar, 1-deoxynojirimycin (23), exhibited inhibitory activity (Ki = 4-10 µM) equal to that of the parent compound (1, Ki = 14 µM). Based on this structure-activity relationship (SAR), four ring-cleaved (26a-26c and 27c) and three truncated (28a-28c) analogues of salacinol (1), a potent thiosugar-ring-containing α-glucosidase inhibitor, were synthesised. Bioassay results revealed that all the synthetics were inactive, indicating that the 5-membered thiosugar ring of 1 played an essential role in the potent activities of sulfonium-type inhibitors. The present findings are interesting and important in understanding the function of salacinol, considering that the observed inhibitory activity trend was contrary to the SAR observed in aza-compounds (23, 24, and 25) in a previous study, which suggested that the cyclic structure did not contribute to their strong inhibitory activity.