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Fialuridine (FIAU) is a nucleoside-based drug that caused liver failure and deaths in a human clinical trial that were not predicted by nonclinical safety studies. A recent report concluded that a TK-NOG humanized liver (hu-liver) mouse model detected human-specific FIAU liver toxicity, and broader use of that model could improve drug safety testing. We further evaluated this model at similar dose levels to assess FIAU sensitivity and potential mechanistic biomarkers. Although we were unable to reproduce the marked acute liver toxicity with two separate studies (including one with a "sensitized" donor), we identified molecular biomarkers reflecting the early stages of FIAU mitochondrial toxicity, which were not seen with its stereoisomer (FIRU). Dose dependent FIAU-induced changes in hu-liver mice included more pronounced reductions in mitochondrial to nuclear DNA (mtDNA/nucDNA) ratios in human hepatocytes compared to mouse hepatocytes and kidneys of the same animals. FIAU treatment also triggered a p53 transcriptional response and opposing changes in transcripts of nuclear- and mitochondrial-encoded mitochondrial proteins. The time dependent accumulation of FIAU into mtDNA is consistent with the ≥9-week latency of liver toxicity observed for FIAU in the clinic. Similar changes were observed in an in vitro micro-patterned hepatocyte coculture system. In addition, FIAU-dependent mtDNA/nucDNA ratio and transcriptional alterations, especially reductions in mitochondrially encoded transcripts, were seen in livers of non-engrafted TK-NOG and CD-1 mice dosed for a shorter period. Conclusion: These mechanistic biomarker findings can be leveraged in an in vitro model and in a more routine preclinical model (CD-1 mice) to identify nucleosides with such a FIAU-like mitochondrial toxicity mechanistic liability potential. Further optimization of the TK-NOG hu-liver mouse model is necessary before broader adoption for drug safety testing. Graphical Abstract FIAU is a nucleoside drug that caused liver failure and deaths in a human clinical trial. FIRU is a diastereomer of FIAU, that has not been shown to induce in vitro toxicity. We tested both compounds in vivo in a TK-NOG humanized liver mouse model with a herpes simplex virus (HSV) thymidine kinase (TK) transgene, in mice without the TK transgene, and in an in vitro human liver model (HepatoPac®). We observed FIAU, but not FIRU-induced decreases in mtDNA/nucDNA ratios in all three models. We also observed a p53 transcriptional response and opposing changes in transcripts of nuclear- and mitochondrial-encoded mitochondrial proteins in mice with the TK transgene and in the in vitro HepatoPac® model. Toxicities of FIAU have been linked to the triphosphate form of this drug. The TK transgene (HSV-TK) may induce cytosolic, but not mitochondrial entrapment of FIAU triphosphate, while mitochondrial thymidine kinase 2 (TK-2) produces FIAU triphosphate that incorporates in mtDNA. [ABSTRACT FROM AUTHOR]

A recyclable bolt is a kind of green supporting component that can save materials and weaken the influence of underground engineering. It has a good application prospect in foundation pit and slope-supporting engineering, as well as a high economic and environmental effect in future engineering construction. The stress and displacement change of the foundation pit with a recoverable bolt was analyzed by performing a laboratory model test. The test results demonstrated that in the process of excavation, the recyclable anchor rod supporting the structure effectively limited the horizontal displacement of the pile top and had a significant constraint effect on the surface settlement. With the increase in the excavation depth, both the axial force value of the recyclable anchor rod and the maximum bending moment value of the supporting pile increased gradually, and the maximum bending moment value of the supporting pile appeared at 1/3 H. After the excavation, the maximum horizontal displacement of the pile top was 0.04% of the excavation depth. The failure recovery of the anchor was the primary factor contributing to the increased deformation of the foundation pit during the backfilling stage. Upon completion of the backfilling process, the final deformation of the foundation pit reached 0.1% of the excavation depth; this can meet safety requirements, reduce the waste of building materials, and conform to the concept of green sustainable development. [ABSTRACT FROM AUTHOR]