Activation of RIG-I/MDA5 Signaling and Inhibition of CD47-SIRPα Checkpoint with a Dual siRNA-Assembled Nanoadjuvant for Robust Cancer Immunotherapy.

Antigen-presenting cells (APCs) play a crucial role in the anti-tumor immunity as they are responsible for capturing, processing, and presenting tumor antigens to T cells. However, their activation is often limited by the absence of adjuvants and the suppressive effects of immune checkpoints, such as CD47-SIRPα. Herein, we present a nanoadjuvant that is self-assembled from long RNA building blocks generated through rolling circle transcription (RCT) reaction and further modified with cationic liposomes. Owing to the high load of densely packed RNA, this nanoadjuvant could robustly activate RIG-I/MDA5 signaling in APCs, leading to the maturation of dendritic cells (DCs) and the polarization of tumor-associated macrophages (TAMs) toward an anti-tumor M1-like phenotype. In addition, with a well-designed template, the generated long RNA from RCT reaction includes two kinds of siRNA targeting both CD47 in tumor cells and SIRPα in APCs. This dual gene silencing results in efficient inhibition of the CD47-SIRPα checkpoint. Collectively, the robust activation of RIG-I/MDA5 signaling and efficient inhibition of CD47-SIRPα checkpoint enhance the phagocytic activity of APCs, which in turn promotes the cross-priming of effector T cells and the activation of anti-tumor immune responses. This study therefore provides a simple and robust RNA nanoadjuvant for cancer immunotherapy.

TG/HDL-c ratio as a predictor of progressive infarction in patients with anterior circulation single subcortical infarction.

BACKGROUND: The contributors predicting progressive infarction (PI) in patients with anterior circulation single subcortical infarction (ACSSI) and pontine single infarction (PSI) may be unidentical. The role of triglyceride to high-density lipoprotein cholesterol (TG/HDL-c) ratio on PI is unclear. The purpose of our study is to evaluate the correlation between TG/HDL-c ratio and PI in patients with ACSSI or PSI. METHODS: Between January 2020 and October 2022, we retrospectively enrolled 738 patients including 638 ACSSI patients and 100 PSI patients to analyze. Demographic characteristics, clinical information, and laboratory data were collected within 24 h of admission. RESULTS: PI occurred in 143 (19.4%) patients. In univariate analysis, patients with PI had higher initial National Institutes of Health Stroke Scale (NIHSS) scores, higher discharge NIHSS scores, higher levels of fasting glucose, total cholesterol, TG, low-density lipoprotein cholesterol, and TG/HDL-c ratio, but lower levels of creatinine compared to patients with non-PI (p < .05). Furthermore, the results of the subgroup analyses revealed the independent association between TG/HDL-c ratio and PI in ACSSI patients (OR 1.079, 95% CI 1.009-1.153, p = .026) rather than in PSI patients. Additionally, a receiver operating characteristic curve indicated that the optimal predictive cutoff value of the TG/HDL-c ratio was 3.985, and a TG/HDL-c ratio ≥3.985 was more likely to experience PI in ACSSI patients. CONCLUSION: In conclusion, the TG/HDL-c ratio was independently associated with PI in patients with ACSSI.

Modular Prodrug-Engineered Oxygen Nano-Tank With Outstanding Nanoassembly Performance, High Oxygen Loading, and Closed-Loop Tumor Hypoxia Relief.

The clinical translation of tumor hypoxia intervention modalities still falls short of expectation, restricted by poor biocompatibility of oxygen-carrying materials, unsatisfactory oxygen loading performance, and abnormally high cellular oxygen consumption-caused insufficient hypoxia relief. Herein, a carrier-free oxygen nano-tank based on modular fluorination prodrug design and co-assembly nanotechnology is elaborately exploited, which is facilely fabricated through the molecular nanoassembly of a fluorinated prodrug (FSSP) of pyropheophorbide a (PPa) and an oxygen consumption inhibitor (atovaquone, ATO). The nano-tank adeptly achieves sufficient oxygen enrichment while simultaneously suppressing oxygen consumption within tumors for complete tumor hypoxia alleviation. Significant, the fluorination module in FSSP not only confers favorable co-assemblage of FSSP and ATO, but also empowers the nanoassembly to readily carry oxygen. As expected, it displays excellent oxygen carrying capacity, favorable pharmacokinetics, on-demand laser-triggerable ATO release, closed-loop tumor hypoxia relief, and significant enhancement to PPa-mediated PDT in vitro and in vivo. This study provides a novel nanotherapeutic paradigm for tumor hypoxia intervention-enhanced cancer therapy.

A novel score to predict progression in anterior circulation single subcortical infarction patients.

OBJECTIVE: Progressive infarction (PI) has a negative effect on functional prognosis. Our study aimed to develop and validate a risk score for predicting PI in patients with anterior circulation single subcortical infarction (ACSSI). METHODS: Between January 2020 and October 2022, we retrospectively enrolled 638 eligible patients with ACSSI. Two-thirds of the eligible patients were randomly allocated to the training cohort (n = 425). Another resampling sample was formed through the bootstrap method and was used as the validation group (n = 425). Multivariate logistic regression analysis was used to identify the independent factors associated with PI. Each factor was then point assigned based on ß-coefficient and a risk scoring system was developed. This scoring system was internally validated through 1000-bootstrap resamplings. The C-statistic and Hosmer-Lemeshow test were used to assess model discrimination and calibration. RESULTS: PI occurred in 121 patients, accounting for 19.0% of the total patients. A 7-point NTS score system based on the initial NIHSS score, triglyceride-glucose index, and the number of infarct slices on axial diffusion-weighted imaging was developed. The NTS score showed good discrimination and calibration in the training cohort (C-statistic = 0.686; p value of Hosmer-Lemeshow test = 0.797) and validation cohort (C-statistic = 0.681; p value of Hosmer-Lemeshow test = 0.451). The three risk levels for predicting PI in the training and validation cohorts based on NTS score were as follows: low (0-2, 9.6% vs. 9.3%), intermediate (3-5, 28.2% vs. 26.7%), and high risk (6-7, 60.2% vs. 57.4%). INTERPRETATION: The NTS score is a valid and convenient risk score for predicting PI in ACSSI patients.

Metal complexes induced ferroptosis for anticancer therapy.

Metal complexes for anti-tumor treatment have been developed rapidly in recent decades since the application of cisplatin in clinics. However, some tumor cells are resistant to apoptosis and not sensitive to metallodrugs that function through the apoptotic pathway. Recently, metal complexes have been reported to cause ferroptosis against tumor cells, which offers new opportunities for anticancer therapy. In this perspective, ferroptosis-inducing metal complexes and their working mechanisms are introduced, while the challenges and opportunities are also discussed.