Ribosomal proteins have emerged as novel regulators of the Mdm2-p53 feedback loop, especially in the context of ribosomal stress. RPS26 is a recently identified Diamond-Blackfan Anemia-related ribosomal protein and its role in p53 activation has not been previously explored. In this study we found knockdown of RPS26 induced p53 stabilization and activation via a RPL11-dependent mechanism, resulting in p53-dependent cell growth inhibition. Moreover, RPS26 has the ability to interact with Mdm2 and inhibits Mdm2-mediated p53 ubiquitination that leads to p53 stabilization upon overexpression. Importantly, we discovered that RPS26 knockdown impaired p53's ability to transcriptionally activate its target genes in response to DNA damage, without affecting its stability. Accordingly, the cells lost the ability to induce G2/M cell cycle arrest. We further found that upon RPS26 knockdown, the DNA damage induced recruitment of p53 to the promoters of its target genes and p53 acetylation were both greatly reduced. In addition, RPS26 can interact with p53 independent of Mdm2 and coexist in a complex with p53 and p300. These data establish a role of RPS26 in DNA damage response by directly influencing p53 transcriptional activity, and suggest that RPS26 acts distinctively in different scenarios of p53 activation. Our finding also implicates p53 transcriptional activity control as an important mechanism of p53 regulation by ribosomal proteins.

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.

Objective: To evaluate the impact of the first round of the National Centralized Drug Procurement (NCDP) pilot (referred to as "4+7" policy) on the use of policy-related original and generic drugs. Methods: Drug purchase data from the China Drug Supply Information Platform (CDSIP) database were used, involving nine "4+7" pilot cities and 12 non-pilot provinces in China. "4+7" policy-related drugs were included, which consisted of 25 "4+7" List drugs and 97 alternative drugs that have an alternative relationship with "4+7" List drugs in clinical use. "4+7" List drugs were divided into bid-winning and non-winning products according to the bidding results. Purchase volume, purchase expenditures, daily costs were selected as outcome variables, and were measured using Defined Daily Doses (DDDs), Chinese Yuan (CNY), and Defined Daily Drug cost (DDDc), respectively. Difference-in-Difference (DID) method was employed to estimate the net effect of policy impact. Results: After policy intervention, the DDDs of original drugs among "4+7" List drugs significantly reduced by 124.59%, while generic drugs increased by 52.12% (all p-values <0.01). 17.08% of the original drugs in DDDs were substituted by generic drugs. Prominent reductions of 121.69% and 80.54% were observed in the expenditure of original and generic drugs, with a total cost-saving of 5036.78 million CNY for "4+7" List drugs. The DDDc of bid-winning original and generic drugs, as well as non-winning original drugs, significantly decreased by 33.20%, 75.74%, and 5.35% (all p-values <0.01), while the DDDc of non-winning generic drugs significantly increased by 73.66% (p<0.001). The use proportion of bid-winning products and non-winning original drugs raised prominently from 39.66% to 91.93% Conclusions: "4+7" policy promoted the substitution use of generic drugs against original drugs, which conducive to drug costs saving. The overall quality level of drug use of public medical institutions significantly increased after "4+7" policy, especially in primary medical institutions.

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