Tumors often respond favorably to initial chemotherapy but eventually relapse with drug resistance and increased metastatic potential. Cellular senescence is a major therapeutic outcome of cancer chemotherapy, which leads to tumor stasis or regression through immune clearance of senescent cells. However, senescent tumor cells have been shown to resume proliferation at low frequency. We found that subjecting arrested senescent tumor cells to cytotoxic treatments stimulates the clonogenic proliferation of remaining survivors. The senescence revertants showed a reduced rate of proliferation but increased migration and invasion potential in vitro, and increased tumorigenic potential in vivo. Gene expression profiling showed that the senescence revertants are distinct from both parental and senescent cells. A subset of senescence-activated genes remains active in the revertants. These genes are implicated in regulating cell motility, invasion, and metastasis, which may collectively contribute to the aggressiveness of the revertants. The findings suggest that although therapy-induced senescence has short-term benefits, the response also causes reprogramming of gene expression and activates invasion-related genes that accelerate tumor progression.

The use of peptidomimetic scaffolds is a promising strategy for the inhibition of protein–protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides can be rationally designed to mimic the p53 α-helix and inhibit p53–MDM2 PPIs. The best inhibitor, with K d and IC50 values of 26 nM and 0.891 μM toward MDM2, respectively, is among the most potent unnatural peptidomimetic inhibitors disrupting the p53–MDM2/MDMX interaction. Using fluorescence polarization assays, circular dichroism, nuclear magnetic resonance spectroscopy, and computational simulations, we demonstrate that sulfono-γ-AApeptides adopt helical structures resembling p53 and competitively inhibit the p53–MDM2 interaction by binding to the hydrophobic cleft of MDM2. Intriguingly, the stapled sulfono-γ-AApeptides showed promising cellular activity by enhancing p53 transcriptional activity and inducing expression of MDM2 and p21. Moreover, sulfono-γ-AApeptides exhibited remarkable resistance to proteolysis, augmenting their biological potential. Our results suggest that sulfono-γ-AApeptides are a new class of unnatural helical foldamers that disrupt PPIs.

As compared with ACCF with plate fixation, ACDF with plate fixation showed no significant differences in terms of postoperative JOA score, fusion rate, but better improved cervical lordosis, lower complication and smaller surgical trauma. As the limitations of small sample and short follow-up in this study, it still could not be identified whether ACDF with plate fixation is more effective and safer than ACCF with plate fixation.

As compared to bilateral PS fixation with cage fusion, unilateral PS fixation with cage fusion achieves a similar VAS, ODI and SF-36 scores, fusion rate, complications and smaller surgical trauma. However, it is still uncertain whether unilateral pedicle screw fixation with cage fusion is as effective and safe as bilateral pedicle screw fixation with cage fusion.

Background: NMNAT1 catalyzes the last step in NAD ϩ synthesis.

Nucleomethylin (NML), a novel nucleolar protein, is important for mediating the assembly of the energy-dependent nucleolar silencing complex (eNoSC), which also contains SirT1 and SUV39H1. eNoSC represses rRNA transcription during nutrient deprivation, thus reducing energy expenditure and improving cell survival. We found that NML is an RNA binding protein that copurifies with 5S, 5.8S, and 28S rRNA. The SirT1 and RNA binding regions on NML showed partial overlap, and the NML-SirT1 interaction was competitively inhibited by rRNA. Nutrient deprivation triggered downregulation of rRNA transcription, reduced the level of NML-associated rRNA, and stimulated NML-SirT1 binding. Assembly of eNoSC facilitated repression of prerRNA transcription. These results suggest that nascent rRNA generates a positive-feedback signal by suppressing the assembly of eNoSC and protecting active ribosomal DNA units from heterochromatin formation. This RNA-mediated mechanism enables the eNoSC to amplify the effects of upstream nutrient-responsive regulators.

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