Within bacterial populations, a small fraction of persister cells is transiently capable of surviving exposure to lethal doses of antibiotics. As a bet-hedging strategy, persistence levels are determined both by stochastic induction and by environmental stimuli called responsive diversification. Little is known about the mechanisms that link the low frequency of persisters to environmental signals. Our results support a central role for the conserved GTPase Obg in determining persistence in Escherichia coli in response to nutrient starvation. Obg-mediated persistence requires the stringent response alarmone (p)ppGpp and proceeds through transcriptional control of the hokB-sokB type I toxin-antitoxin module. In individual cells, increased Obg levels induce HokB expression, which in turn results in a collapse of the membrane potential, leading to dormancy. Obg also controls persistence in Pseudomonas aeruginosa and thus constitutes a conserved regulator of antibiotic tolerance. Combined, our findings signify an important step toward unraveling shared genetic mechanisms underlying persistence.

This study aims to construct the stromal immunotype, which could improve the prediction of postsurgical survival and adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer (MIBC). A total of 118 patients with MIBC from Shanghai Cancer Center, 140 patients with MIBC from Zhongshan Hospital, and 287 patients with MIBC from TCGA cohort were included in the study. Immune cell infiltration was evaluated by IHC staining or CIBERSORT method. Five immune features were selected out of 22 immune features to construct immunotypes based on the LASSO Cox regression model. Using the LASSO model, we classified patients with MIBC into stromal immunotype A subgroup (CTLNKTregMacrophageMC) and stromal immunotype B subgroup (CTLNKTregMacrophageMC). Significant differences were found between immunotype A and immunotype B in the combined cohort with 5-year overall survival (OS, 76.0% vs. 44.0%; < 0.001) and 5-year disease-free survival (DFS, 62.8% vs. 48.3%; < 0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately. Either OS or DFS was not improved by adjuvant chemotherapy (ACT) in pT2 stage patients or pT3+pT4 patients, but further analysis revealed that OS and disease-free was significantly improved by ACT in pT3+pT4 patients ( = 0.016 and = 0.006, respectively). Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) expression. The stromal immunotypes could effectively predict survival and recurrence of MIBC. Furthermore, the immunotypes might be a practical predictive tool to identify pT3+pT4 patients who would benefit from ACT. .

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Combination chemotherapy has been proven promising for cancer treatment, but unsatisfactory therapeutic data and increased side effects slow down the development in the clinic. In this study, we develop an effective approach to co-encapsulate a hydrophilic-hydrophobic chemotherapeutic drug pair (paclitaxel and doxorubicin) into magnetic O-carboxymethyl-chitosan nanoparticles. To endow them with the ability of programmed delivery, these carriers are further camouflaged with an Arg-Gly-Asp anchored erythrocyte membrane. Compared with the traditional polyethylene glycol coating method, this biomimetic decoration strategy is demonstrated to be superior in prolonging circulation time, improving tumor accumulation, facilitating tumor uptake, and tuning intracellular fate. These outstanding properties enable the as-designed nanodevice to exhibit greater tumor growth inhibition ability and much lower side effects than the combined use of commercial formulations.