Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

[Review of Comprehensive Evaluation System of Vehicle Pollution and Carbon Synergistic Reduction].

Vehicle emissions have become one of the most important air pollution sources in China. Promoting vehicle synergistic reduction of pollution and carbon is the key to improving regional environmental quality and achieving the carbon peaking and carbon neutrality goals. Building a collaborative evaluation system and comprehensive quantitative method is an important prerequisite for scientific and effective implementation of vehicle pollution and carbon synergistic reduction. Therefore, it is significant to extensively review existing synergistic evaluation methods and comprehensive environmental benefit accounting methods of atmospheric pollution and carbon reduction. On this basis, we focused on vehicle emission characteristics, systematically organized the key indicators of vehicle collaborative reduction evaluation, and summarized quantitative methods of policy effects from three aspects (health exposure cost, climate change cost, and pollutant control cost), to provide theoretical support for policy formulation, schemes selection, and their effect evaluation. For the future, the assessment of vehicle coordinated emission reduction is proposed to accelerate unified index system establishment, deeply analyze the spatial distribution of environmental benefits, focus on the pollution transfer caused by vehicle electrification, and explore the quantitative methods of climate change cost due to extreme weather.

OPM-MEG Measuring Phase Synchronization on Source Time Series: Application in Rhythmic Median Nerve Stimulation.

The magnetoencephalogram (MEG) based on array optically pumped magnetometers (OPMs) has the potential of replacing conventional cryogenic superconducting quantum interference device. Phase synchronization is a common method for measuring brain oscillations and functional connectivity. Verifying the feasibility and fidelity of OPM-MEG in measuring phase synchronization will help its widespread application in the study of aforementioned neural mechanisms. The analysis method on source-level time series can weaken the influence of instantaneous field spread effect. In this paper, the OPM-MEG was used for measuring the evoked responses of 20Hz rhythmic and arrhythmic median nerve stimulation, and the inter-trial phase synchronization (ITPS) and inter-reginal phase synchronization (IRPS) of primary somatosensory cortex (SI) and secondary somatosensory cortex (SII) were analysed. The results find that under rhythmic condition, the evoked responses of SI and SII show continuous oscillations and the effect of resetting phase. The values of ITPS and IRPS significantly increase at the stimulation frequency of 20Hz and its harmonic of 40Hz, whereas the arrhythmic stimulation does not exhibit this phenomenon. Moreover, in the initial stage of stimulation, the ITPS and IRPS values are significantly higher at Mu rhythm in the rhythmic condition compared to arrhythmic. In conclusion, the results demonstrate the ability of OPM-MEG in measuring phase pattern and functional connectivity on source-level, and may also prove beneficial for the study on the mechanism of rhythmic stimulation therapy for rehabilitation.

Refining the 8th edition TNM classification for EBV related nasopharyngeal carcinoma.

The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.