Mutual promotion of co-condensation of KRAS G-quadruplex and a well-folded protein HMGB1.

Liquid-liquid phase separation (LLPS) of G-quadruplex (GQ) is involved in many crucial cellular processes, while the quadruplex-folding and their functions are typically modulated by specific DNA-binding proteins. However, the regulatory mechanism of binding proteins, particularly the well-folded proteins, on the LLPS of GQs is largely unknown. Here, we investigated the effect of HMGB1 on the condensation of a G-quadruplex of KRAS promoter (GQKRAS). The results show that these two rigid macro-biomolecules undergo co-condensation through a mutual promotion manner, while neither of them can form LLPS alone. Fluidity measurements confirm that the liquid-like droplets are highly dynamic. HMGB1 facilitates and stabilizes the quadruplex folding of GQKRAS, and this process enhances their co-condensation. The KRAS promoter DNA retains quadruplex folding in the droplets; interference with the GQ-folding disrupts the co-condensation of GQKRAS/HMGB1. Mechanistic studies reveal that electrostatic interaction is a key driving force of the interaction and co-condensation of GQKRAS/HMGB1; meanwhile, the recognition of two macro-biomolecules plays a crucial role in this process. This result indicates that the phase separation of GQs can be modulated by DNA binding proteins, and this process could also be an efficient way to recruit specific DNA binding proteins.

Clinical characteristics of bloodstream infections in adult patients with solid tumours and a nomogram for mortality prediction: a 5-year case-controlled retrospective study in a tertiary-level hospital.

Background: Bloodstream infections (BSIs) are one of the leading causes of death in cancer patients. Nevertheless, the risk factors of BSIs in solid tumors have rarely been ascertained adequately. Methods: We conducted a single-center case-controlled retrospective study from 2017 to 2021 among adults with solid tumors in a tertiary-level hospital. The BSIs and control group were matched by the propensity score matching method. We found independent risk factors of occurrence and death of BSIs using univariate and multivariate regression analysis. Additionally, a nomogram was constructed to predict the risk of mortality in BSIs. Results: Of 602 patients with solid tumors in the study period, 186 had BSIs and 416 had non-BSIs. The incidence of BSIs was 2.0/1,000 admissions (206/102,704), and the 30-day mortality rate was 18.8% (35/186). Compared to the control group, the BSIs had longer hospital stays (24.5 days vs. 20.0 days), and higher frequency complicating with organ failure (10.5% vs. 2.4%), nephropathy (19.6% vs. 3.8%), comorbidities≥3 (35.5% vs. 20.0%), and liver-biliary-pancreatic infections (15.6% vs. 5.3%) (all P<0.001). Among the 186 patients with BSIs, 35 died within 30 days after BSIs. Gram-negative bacteria were the most frequent microorganisms (124/192, 64.6%). Liver cancer, organ failure, a high level of lactate dehydrogenase and septic shock were the independent hazardous factors for death of BSIs. What's more, a nomogram was constructed to predict the 30-day survival rate of BSIs, which was proved to have good accuracy (AUC: 0.854; 95% confidence interval: 0.785~0923) and consistency. Conclusion: Being aware of the risk factors of BSIs redounds to take preventive measures to reduce the incidence and death of BSIs.

Photothermal Enhanced and Tumor Microenvironment Responsive Nanozyme for Amplified Cascade Enzyme Catalytic Therapy.

Nanocatalysts, a class of nanomaterials with intrinsic enzyme-like activities, have been widely investigated for cancer catalytic therapy in recent years. However, precise construction of nanocatalysts with excellent enzyme catalytic activity and biosafety for tumor therapy still remains challenging. Here, a biodegradable nanocatalyst, PEGylated Cux Mny Sz (PCMS), is reported that can promote cascade catalytic reactions in tumor microenvironment (TME) while confining off-target side effects on normal tissues. PCMS not only catalyzes the cascade conversion of endogenous hydrogen peroxide (H2 O2 ) to oxygen (O2 ) via catalase-like activity and then to superoxide radical (·O2 - ) via oxidase-like activity in the TME, but also effectively depletes intracellular glutathione via glutathione oxidase-like activity. The cascade catalytic reactions, by taking advantage of high H2 O2 level in tumor cells, result in an enhanced enzyme catalytic effect in generation of ·O2 - . More importantly, PCMS exhibits prominent photothermal effect under NIR-II 1064 nm laser irradiation that can further enhance chemodynamic therapy (CDT) efficacy in tumors. In addition, the biodegradation in TME and excellent photothermal effect of PCMS are beneficial to magnetic resonance imaging, photoacoustic imaging and infrared thermal imaging, resulting in tracing the fate of PCMS in vivo. This study provides a new tool for rational design of TME-responsive nanocatalysts with high biocompatibility for tumor catalytic therapy.