Drivers and impacts of decreasing concentrations of atmospheric volatile organic compounds (VOCs) in Beijing during 2016-2020.

China has implemented various policies and measures for controlling air pollutants. However, our knowledge of the long-term trends in ambient volatile organic compounds (VOCs) after the implementation of these action plans in China remains limited. To address this, we conducted a five-year analysis (2016-2020) of VOC compositions and concentrations in Beijing. The annual VOC concentration decreased from 44.0 ± 28.8 to 26.2 ± 16.4 ppbv, with alkanes being the most prevalent group. The annual average concentrations of alkenes, alkynes, and aromatics have experienced a significant decrease of over 50 %. Seasonal variations indicated higher VOC concentrations in winter and autumn, with more significant reductions observed in winter and autumn. The impact of meteorological conditions caused variations in VOC reductions during the Chinese Spring Festival. Satellite-based measurements of formaldehyde (HCHO) columns confirmed the reduction of VOC emissions during the Coronavirus (COVID-19) lockdown. The normalized annual average VOC concentration decreased by 2.9ppbv yr-1 from 2016 to 2020, and emission reduction contributed to 58.8 % of VOC reduction from 2016 to 2020 after meteorological normalization, indicating the effectiveness of implemented control measures. Based on receptor model, vehicle emissions and industrial sources were identified as the largest contributors to VOC concentrations. Vehicle emissions, liquefied petroleum gas/natural gas (LPG/NG) use, and coal combustion were major drivers of VOC reduction. Potential source region analysis revealed that air masses transported from northwestern and southern regions significantly contributed to VOC concentrations in Beijing. The range of source regions shrunk in both northwestern and southern regions with the reduction in VOC concentrations. The annual variations of ozone formation potential indicated a significant decrease in VOC reactivities through emission control. These results could provide insights into future emission control and coordinated efforts to improve PM2.5 and ozone levels in China.

Smart antioxidant function enhancing (SAFE) nucleic acid therapy for ROS-related chronic diseases and comorbidities.

Reactive oxygen species (ROS)-mediated oxidative stress exacerbates chronic diseases such as organ damage and neurodegenerative disorders. The Keap1-Nrf2-ARE pathway is a widely distributed endogenous antioxidant system. However, ROS under redox homeostasis regulates a wide range of life activities. Therefore, smart scavenging of excess ROS under pathological conditions is essential to treat chronic diseases safely. This study reports a smart antioxidant function enhancement (SAFE) strategy. On-demand release of nucleic acid drugs in a pathological ROS environment smartly activates the endogenous antioxidant system, thereby smartly alleviating oxidative stress in an exogenous antioxidant-independent manner. Through structural modulation and ligand modification, we develop SAFE nanoparticles based on nanohybrid complexes (SAFE-complex) adapted to brain delivery of nucleic acid drugs. SAFE-complex with homogeneous monodisperse structure efficiently treat ROS-related neurodegenerative diseases while protecting the major organ from oxidative stress damage. Moreover, SAFE-complex can stabilize storage in the form of freeze-dried powder. These data indicate that SAFE nanoparticles hold promise for treating ROS-related chronic diseases and comorbidities through rational transformation.

Unveiling the metal mutation nexus: Exploring the genomic impacts of heavy metal exposure in lung adenocarcinoma and colorectal cancer.

Mutations that activate oncogenes and deactivate tumor suppressor genes are widely recognized as significant contributors to cancer development. We investigated relationships between heavy metal exposure and the frequencies and types of gene mutations in patients with lung adenocarcinoma (LUAD) and colorectal cancer (CRC). Plasma concentrations of arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), and lead (Pb) were measured using inductively coupled plasma mass spectrometry (ICPMS), and next-generation sequencing (NGS) of 1123 cancer-related genes was performed using the tumor tissues. Through Bayesian kernel machine regression (BKMR) analysis, we found associations between the integrated concentrations of the heavy metals and the number of gene mutations, especially insertions/deletions (indels), and Pb, As, and Cd were found to be the most significant contributors to the increased mutation rates. We extracted previously established mutational signatures and observed that they exhibit significant correlations with metal exposure. Moreover, we detected substantial shifts in the mutational landscape when comparing groups with high and low metal exposures. Several frequently mutated genes displayed positive correlations with metal exposure, whereas EGFR indels showed a negative association with Cd exposure. These findings suggest that heavy metal exposure can impact genomic stability in cancer-related genes, underscoring the importance of heavy metal exposure in cancer development.

Real-time, single-particle chemical composition, volatility and mixing state measurements of urban aerosol particles in southwest China.

To investigate the volatility of atmospheric particulates and the evolution of other particulate properties (chemical composition, particle size distribution and mixing state) with temperature, a thermodenuder coupled with a single particle aerosol mass spectrometer was used to conduct continuous observations of atmospheric fine particles in Chengdu, southwest China. Because of their complex sources and secondary reaction processes, the average mass spectra of single particles contained a variety of chemical components (including organic, inorganic and metal species). When the temperature rose from room temperature to 280°C, the relative areas of volatile and semi-volatile components decreased, while the relative areas of less or non-volatile components increased. Most (> 80%) nitrate and sulfate existed in the form of NH4NO3 and (NH4)2SO4, and their volatilization temperatures were 50-100°C and 150-280°C, respectively. The contribution of biomass burning (BB) and vehicle emission (VE) particles increased significantly at 280°C, which emphasized the important role of regional biomass burning and local motor vehicle emissions to the core of particles. With the increase in temperature, the particle size of the particles coated with volatile or semi-volatile components was reduced, and their mixing with secondary inorganic components was significantly weakened. The formation of K-nitrate (KNO3) and K-sulfate (KSO4) particles was dominated by liquid-phase processes and photochemical reactions, respectively. Reducing KNO3 and BB particles is the key to improving visibility. These new results are helpful towards better understanding the initial sources, pollution formation mechanisms and climatic effects of fine particulate matter in this megacity in southwest China.

Ratiometrically electrochemical and colorimetric dual-mode detection of glyphosate based on 2D Cu-TCPP(Fe) NSs.

In this work, a dual-signal output sensor was developed for the ratiometrically electrochemical and colorimetric detection of glyphosate (GLYP) based on the duplex nature of 2D Cu-TCPP(Fe) nanosheets (2D Cu-TCPP(Fe) NSs). Cu active center sites in 2D Cu-TCPP(Fe) NSs could transform into CuCl for signal amplification in the presence of chloride ions (Cl-), which dropped dramatically upon GLPY addition due to the strong interaction between GLYP and cuprous ion triggering the competitive reaction with the conversion of CuCl into Cu-GLYP complex. Meanwhile, the constant current signals of Fe2+/3+ in the iron-porphyrin structure of Cu-TCPP(Fe) served as an inner reference, resulting in a ratiometrically electrochemical GLYP sensor. Moreover, 2D Cu-TCPP(Fe) NSs with intrinsic peroxidase-like activity was employed for the colorimetric determination of GLYP based on the specific inhibitory effect of GLYP on the peroxidase activity of 2D Cu-TCPP(Fe) nanozyme. GLYP concentrations can be quantified in the range from 1.0 × 10-10 M to 1.0 × 10-6 M and 1.0 × 10-9 M to 1.0 × 10-7 M, with detection limits of 3.9 × 10-12 M and 1.89 × 10-11 M for ratiometrically electrochemical method and colorimetric assay, respectively. Such a dual-mode sensor with remarkable selectivity, reproducibility, and stability was finally applied for GLYP detection in real samples and reliable outcomes were achieved.

Morphological disruption and visual tuning alterations in the primary visual cortex in glaucoma (DBA/2J) mice.

Glaucoma is a leading cause of irreversible blindness worldwide, and previous studies have shown that, in addition to affecting the eyes, it also causes abnormalities in the brain. However, it is not yet clear how the primary visual cortex (V1) is altered in glaucoma. This study used DBA/2J mice as a model for spontaneous secondary glaucoma. The aim of the study was to compare the electrophysiological and histomorphological characteristics of neurons in the V1 between 9-month-old DBA/2J mice and age-matched C57BL/6J mice. We conducted single-unit recordings in the V1 of light-anesthetized mice to measure the visually induced responses, including single-unit spiking and gamma band oscillations. The morphology of layer II/III neurons was determined by neuronal nuclear antigen staining and Nissl staining of brain tissue sections. Eighty-seven neurons from eight DBA/2J mice and eighty-one neurons from eight C57BL/6J mice were examined. Compared with the C57BL/6J group, V1 neurons in the DBA/2J group exhibited weaker visual tuning and impaired spatial summation. Moreover, fewer neurons were observed in the V1 of DBA/2J mice compared with C57BL/6J mice. These findings suggest that DBA/2J mice have fewer neurons in the V1 compared with C57BL/6J mice, and that these neurons have impaired visual tuning. Our findings provide a better understanding of the pathological changes that occur in V1 neuron function and morphology in the DBA/2J mouse model. This study might offer some innovative perspectives regarding the treatment of glaucoma.

Saying no to SARS-CoV-2: the potential of nitric oxide in the treatment of COVID-19 pneumonia.

Nitric oxide (NO), a gaseous free radical produced from L-arginine catalyzed by NO synthase, functions as an important signaling molecule in the human body. Its antiviral activity was confirmed in the 1990s, and has been studied more extensively since the outbreak of the SARS pandemic in 2003. In the fight against the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, some recent studies have revealed the potential of NO in the treatment of coronavirus disease 2019 (COVID-19). The progress in this field, including several noteworthy clinical trials of inhaled NO for the treatment of COVID-19 and the emergency approval of NO nasal spray by the regulatory agencies of Israel, Bahrain, Thailand and Indonesia for the treatment of COVID-19 pneumonia, offers a new perspective for addressing the raging coronavirus infection and greatly broadens the clinical application of NO therapy. This review aims to explore the underlying molecular mechanisms of NO-based therapy against SARS-CoV-2, including direct viral inhibition, immune regulation, and protection against pulmonary and cardiovascular symptoms. Furthermore, the potential therapeutic applications of inhaled NO, NO donors and drugs involved in the NO pathway are discussed. In the context of a global vaccination campaign and newly proposed strategy of "coexistence with COVID-19," the advantages of NO therapies as symptomatic and adjuvant treatments are expected to deliver breakthroughs in the treatment of COVID-19.

Melatonin alleviates Hg toxicity by modulating redox homeostasis and the urea cycle in moss.

Mercury (Hg) is a highly toxic metal and can cause severe damage to many organisms under natural conditions. As an effective free radical scavenger and antioxidant, Melatonin (MT) has played important protective roles in alleviating oxidative damage caused by environmental cues including heavy metal stress in plants. However, the detailed mechanisms of melatonin in alleviating Hg toxicity still remain unclear in plants. Our results showed that the application of melatonin greatly reduced the concentrations of total and intracellular Hg in Taxiphyllum taxirameum. Meanwhile, melatonin significantly improved the antioxidant capacity and thus alleviated oxidative damage to the chloroplasts of T. taxirameum under Hg stress. Metabolic pathway analysis further revealed that melatonin-treated plants exhibited higher levels of 48 metabolites, including sugars, amino acids, and lipids, than non-melatonin-treated plants under Hg stress. Additionally, we further found that melatonin addition greatly improved the concentrations of four organic acids and three amino acids (Orn, Cit and Arg) related to the urea cycle, and thereby changed the levels of putrescine (Put) and spermidine (Spd) in T. taxirameum exposed to Hg stress. Further experiments showed that the high concentration of Put dramatically caused oxidative damage under Hg stress, while Spd effectively alleviated Hg toxicity in T. taxirameum. Taken together, this study provides new insight into the underlying mechanisms of melatonin in alleviating heavy metal toxicity in plants.

Hydroxyl-group functionalized phenanthroline diimides as efficient masking agents for Am(III)/Eu(III) separation under harsh conditions.

The separation of Lns(III) from radioactive Ans(III) in high-level liquid waste remains a formidable hydrometallurgical challenge. Water-soluble ligands are believed to be new frontiers in the search of efficient Lns/Ans separation ligands to close the nuclear fuel cycles and dealing with current existing nuclear waste. Currently, the development of hydrophilic ligands far lags behind their lipophilic counterparts due to their complicated synthetic procedures, inferior extraction performances, and acid tolerances. In this paper, we have showed a series of hydroxyl-group functionalized phenanthroline diimides were efficient masking agents for Am(III)/Eu(III) separation under high acidity (˃ 1 M HNO3). Record high SFEu(III)/Am(III) of 162 and 264 were observed for Phen-2DIC2OH and Phen-2DIC4OH in 1.25 M HNO3 which represents the best Eu(III)/Am(III) separation performance at this acidity. UV-vis absorption, NMR and TRLFS titrations were conducted to elucidate the predominant of 1:1 ligand/metal species under extraction conditions. X-ray data of both the ligand and Eu(III) complex together with DFT calculations revealed the superior extraction performances and selectivities. The current reported hydrophilic ligands were easy to prepare and readily to scale-up, acid tolerant and highly efficient, together with their CHON-compatible nature make them promising candidates in the development of advanced separation processes.

Quantitative study of ternary polycrystalline mixtures of prulifloxacin based on Raman spectra and Raman imaging maps.

Prulifloxacin, a broad-spectrum quinolone antibiotic, exhibits three distinct crystal forms, each with different bioavailability and therapeutic properties. It is imperative to assess and control the proportion of each crystal form during the production of raw materials and preparations. Therefore, it is necessary to establish an analytical method that can determine the content of each crystal form in the ternary polycrystalline mixtures. In this study, prulifloxacin crystal forms were analyzed and quantitatively measured using Raman spectroscopy. First, three pure crystal forms of prulifloxacin were prepared under different crystallization conditions and mixed into ternary mixtures at the designed proportions. Subsequently, the ternary mixed crystal samples were analyzed using a Raman microscope.Then run a partial least squares regression analysis to establish a PLS quantitative model using the average spectra data, and a non-negative least squares analysis to establish an area percentage quantitative model using Raman imaging data.The method validation results showed that the two models successfully predicted the proportion of each crystal form within the prulifloxacin polycrystalline mixtures, with a prediction accuracy of less than ± 10 %. Raman spectroscopy was thus established as an effective method for crystal form analysis and quantitative measurement of prulifloxacin.

Treatment of landfill leachate nanofiltration concentrate by a three-dimensional electrochemical technology with waste aluminum scraps as particle electrodes: Efficacy, mechanisms, and enhancement effect of subsequent electrocoagulation.

Landfill leachate nanofiltration concentrate is a kind of wastewater containing high concentrations of color and refractory organics. Herein, we proposed a novel three-dimensional electrochemical technology (3DET) with waste aluminum scraps as particle electrodes for its treatment. The planar and particle electrodes were first optimized. Ti/RuO2 and graphite were used as anodes in the two-dimensional electrochemical technology (2DET). In the light of contaminant removal (color, UV254, COD, and TOC), chlorine reduction, and energy consumption, graphite was selected as planar anodes and cathodes. Moreover, 3DET with Al particle electrodes (Al 3DET) outperformed that with conventional granular activated carbon electrodes, 2DET, and Al particles. At 120 min, the removal efficiencies of color, UV254, COD, and TOC using Al 3DET were 98.94 %, 84.72 %, 51.93 %, and 67.46 %, respectively. UV-vis and EEM spectroscopy, and GC-MS analyses indicate that macromolecular organic matter such as humic-like substances could be effectively degraded and simultaneously removed. Reactive species identification tests including free radical quenching and EPR spectra were conducted. The results indicate that in addition to anodic direct oxidation, indirect oxidation by oxidative species (H2O2, •OH, and RCS) and flocculation by Al species also played a vital role in contaminant removal. Continuous-flow experiments show that Fe EC as a post-treatment step of Al 3DET could effectively provide a neutralization effect for the 3DET effluent and enhance the removal efficiency of contaminants. The total operating cost of combined process was 1.307 USD/m3. This study shows that the Al 3DET-Fe EC process is a promising technology for the treatment of nanofiltration concentrate.

Ginkgolide B attenuates cerebral ischemia-reperfusion injury via inhibition of ferroptosis through disrupting NCOA4-FTH1 interaction.

ETHNOPHARMACOLOGICAL RELEVANCE: Cerebral ischemia/reperfusion (I/R) injury is a major cause of neuronal damage and death. Ginkgolide B (GB) has been shown to exhibit neuroprotective effects in various brain injury models. AIM OF STUDY: The aim of study was to investigate the potential role of GB in protecting against cerebral I/R injury and explore the underlying mechanisms. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were exposed to transient middle cerebral artery occlusion (tMCAO) followed by reperfusion in order to trigger cerebral I/R injury. The rats were treated with different doses of GB, vehicle control or positive drug. Neurological function, infarct volume, and levels of ferroptosis markers were evaluated. In vitro experiments were performed using OGD/R-induced PC12 cells to further investigate the effects of GB on ferroptosis and its mechanisms. In addition, molecular docking, and microscale thermophoresis (MST) assay were conducted to explore the combination of GB and NCOA4. RESULTS: Reduced infarct volume and enhanced neurological function were signs of dose-dependent protection from cerebral I/R injury by GB therapy. Additionally, GB treatment had an impact on the levels of oxidative stress and ferroptosis markers, including reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and Fe2+ in the cerebral environment during IR injury. Moreover, relevant ferroptosis key factors such as ACSL4, GPX4, FTH1, and NCOA4 can be regulated by GB. In OGD/R-induced PC12 cells, GB protected against ferroptosis by inhibiting autophagy and disrupting the interaction of NCOA4-FTH1. CONCLUSION: Our findings suggest that GB may protect against cerebral I/R injury by inhibiting ferroptosis through disrupting NCOA4-FTH1 interaction. GB has potential therapeutic applications for cerebral I/R injury, and further investigation of the underlying mechanisms and clinical trials are warranted.

Comprehensive understanding on sources of high levels of fine particulate nitro-aromatic compounds at a coastal rural area in northern China.

Nitro-aromatic compounds (NACs) are among the major components of brown carbon (BrC) in the atmosphere, causing negative impacts on regional climate, air quality, and ecological health. Due to the extensive origins, it is still a challenge to figure out the contributions and originating regions for different sources of atmospheric NACs. Here, field observations on fine particulate NACs were conducted at a coastal rural area in Qingdao, China in the winter of 2018 and 2019. The mean total concentrations of fine particulate nitro-aromatic compounds were 125.0 ± 89.5 and 27.7 ± 21.1 ng/m3 in the winter of 2018 and 2019, respectively. Among the measured eleven NACs, nitrophenols and nitrocatechols were the most abundant species. Variation characteristics and correlation analysis showed that humidity and anthropogenic primary emissions had significant influences on the NAC abundances. In this study, two tracing methods of the improved spatial concentration weighted trajectory (SCWT) model and the receptor model of positive matrix factorization (PMF) were combined to comprehensively understand the origins of NACs in fine particles at coastal Qingdao. Four major sources were identified, including coal combustion, biomass burning, vehicle exhaust, and secondary formation. Surprisingly, coal combustion was responsible for about half of the observed nitro-aromatic compounds, followed by biomass burning (∼30%). The results by SCWT demonstrated that the coal combustion dominated NACs mainly originated from the Shandong peninsula and the areas to the north and southwest, while those dominated by biomass burning primarily came from local Qingdao and the areas to the west.

X-box binding protein 1 caused an imbalance in pyroptosis and mitophagy in immature rats with di-(2-ethylhexyl) phthalate-induced testis toxicity.

As a widely used plasticizer, di-(2-ethylhexyl) phthalate (DEHP) is known to induce significant testicular injury. However, the potential mechanism and effects of pubertal exposure to DEHP on testis development remain unclear. In vivo, postnatal day (PND) 21 male rats were gavaged with 0, 250, and 500 mg/kg DEHP for ten days. Damage to the seminiferous epithelium and disturbed spermatogenesis were observed after DEHP exposure. Meanwhile, oxidative stress-induced injury and pyroptosis were activated. Both endoplasmic reticulum (ER) stress and mitophagy were involved in this process. Monoethylhexyl phthalate (MEHP) was used as the biometabolite of DEHP in vitro. The GC-1 and GC-2 cell lines were exposed to 0, 100 µM, 200 µM, and 400 µM MEHP for 24 h. Reactive oxygen species (ROS) generation, oxidative stress damage, ER stress, mitophagy, and pyroptosis were significantly increased after MEHP exposure. The ultrastructure of the ER and mitochondria was destroyed. X-box binding protein 1 (XBP1) was observed to be activated and translocated into the nucleus. ROS generation was inhibited by acetylcysteine. The levels of antioxidative stress, ER stress, mitophagy, and pyroptosis were decreased as well. After the administration of the ER stress inhibitor 4-phenyl-butyric acid, both mitophagy and pyroptosis were inhibited. Toyocamycin-induced XBP1 down-regulation decreased the levels of mitophagy and pyroptosis. The equilibrium between pyroptosis and mitophagy was disturbed by XBP1 accumulation. In summary, our findings confirmed that DEHP induced a ROS-mediated imbalance in pyroptosis and mitophagy in immature rat testes via XBP1. Moreover, XBP1 might be the key target in DEHP-related testis dysfunction.

Nonreciprocal reflection based on asymmetric graphene metasurfaces.

We propose a scheme to achieve controllable nonreciprocal behavior in asymmetric graphene metasurfaces composed of a continuous graphene sheet and a poly crystalline silicon slab with periodic grooves of varying depths on each side. The proposed structure exhibits completely asymmetric reflection in opposite directions in the near-infrared range, which is attributed to the pronounced structural asymmetry and its accompanying nonlinear effects. The obtained nonreciprocal reflection ratio, reaching an impressive value of 21.27 dB, combined with a minimal insertion loss of just -0.76 dB, highlights the remarkable level of nonreciprocal efficiency achieved by this design compared to others in its category. More importantly, the proposed design can achieve dynamic tunability by controlling the incident field intensity and the graphene Fermi level. Our design highlights a potential means for creating miniaturized and integratable nonreciprocal optical components in reflection mode, which can promote the development of the integrated isolators, optical logic circuits, and bias-free nonreciprocal photonics.

Cuproptosis-related gene LIPT1 as a prognostic indicator in non-small cell lung cancer: Functional involvement and regulation of ATOX1 expression.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, necessitating a deeper understanding of novel cell death pathways like cuproptosis. This study explored the relevance of cuproptosis-related genes in NSCLC and their potential prognostic significance. We analyzed the expression of 16 cuproptosis-related genes in 1017 NSCLC tumors and 578 Genotype-Tissue Expression (GTEx) normal samples from The Cancer Genome Atlas (TCGA) to identify significant genes. A risk model and prognostic nomogram were employed to identify the pivotal prognostic gene. Further in vitro experiments were conducted to investigate the functions of the identified genes in NSCLC cell lines. LIPT1, a gene for lipoate-protein ligase 1 enzyme, emerged as the central prognostic gene with decreased expression in NSCLC. Importantly, elevated LIPT1 levels were associated with a favorable prognosis for NSCLC patients. Overexpression of LIPT1 inhibited cell growth and enhanced apoptosis in NSCLC. We confirmed that LIPT1 downregulates the copper chaperone gene antioxidant 1 (ATOX1), thereby impeding NSCLC progression. Our study identified LIPT1 as a valuable prognostic biomarker in NSCLC as it elucidates its tumor-inhibitory role through the modulation of ATOX1. These findings offered insights into the potential therapeutic targeting of LIPT1 in NSCLC, contributing to a deeper understanding of this deadly disease.

IRX2 regulates endometrial carcinoma oncogenesis by transcriptional repressing RUVBL1.

Endometrial carcinoma (EC) is a rising concern among gynecological malignancies. Iroquois Homeobox 2 (IRX2), a member of the Iroquois homeobox gene family, demonstrates variable effects in different cancer types, emphasizing the need for extensive exploration of its involvement in EC progression. Utilizing TCGA and GEO databases, as well as performing immunohistochemistry (IHC) analysis on clinical samples, we assessed the expression levels of IRX2 and its promoter methylation in EC. To understand the functional roles of IRX2, we conducted various assays including in vitro CCK-8 assays, colony formation assays, cell invasion assays, and cell apoptosis assays. Moreover, we utilized in vivo subcutaneous xenograft mouse models. Additionally, we performed KEGG pathway and gene set enrichment analyses to gain insights into the underlying mechanisms. To validate the regulatory relationship between IRX2 and RUVBL1, we employed chromatin immunoprecipitation and luciferase reporter assays. Our results indicate significantly reduced levels of IRX2 expression in EC, correlating with higher histological grades, advanced clinical stages, and diminished overall survival. We observed that DNA methylation of the IRX2 promoter suppresses its expression in EC, with cg26333652 and cg11793269 playing critical roles as methylated sites. In contrast, ectopic overexpression of IRX2 substantially inhibits cell proliferation and invasion, and promotes cell apoptosis. Additionally, we discovered that IRX2 exerts negative regulation on the expression of RUVBL1, which is upregulated in EC and associated with a poorer prognosis. In conclusion, our findings indicate that decreased expression of IRX2 facilitates EC cell growth through the regulation of RUVBL1 expression, thereby contributing to the development of EC. Hence, targeting the IRX2-RUVBL1 axis holds promise as a potential therapeutic strategy for EC treatment.

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced cervical cancer constitutes around 37% of cervical cancer cases globally and has a poor prognosis due to limited therapeutic options. Immune checkpoint inhibitors in the neoadjuvant setting could address these challenges. We aimed to investigate the efficacy and safety of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer. METHODS: In this single-arm, phase 2 trial, which was done across eight tertiary hospitals in China, we enrolled patients aged 18-70 years with untreated cervical cancer (IB3, IIA2, or IIB/IIIC1r with a tumour diameter ≥4 cm [International Federation of Gynecology and Obstetrics, 2018]) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients underwent one cycle of priming doublet chemotherapy (75-80 mg/m2 cisplatin, intravenously, plus 260 mg/m2 nab-paclitaxel, intravenously), followed by two cycles of a combination of chemotherapy (cisplatin plus nab-paclitaxel) on day 1 with camrelizumab (200 mg, intravenously) on day 2, with a 3-week interval between treatment cycles. Patients with stable disease or progressive disease received concurrent chemoradiotherapy, and patients with a complete response or partial response proceeded to radical surgery. The primary endpoint was the objective response rate, by independent central reviewer according to Response Evaluation Criteria in Solid Tumours, version 1.1. Activity and safety were analysed in patients who received at least one dose of camrelizumab. This study is registered with ClinicalTrials.gov, NCT04516616, and is ongoing. FINDINGS: Between Dec 1, 2020, and Feb 10, 2023, 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46-57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0-14·5). An objective response was noted in 83 (98% [95% CI 92-100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. The most common grade 3-4 treatment-related adverse events during neoadjuvant chemo-immunotherapy were lymphopenia (21 [25%] of 85), neutropenia (ten [12%]), and leukopenia (seven [8%]). No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer. FUNDING: National Key Technology Research and Development Program of China and the National Clinical Research Center of Obstetrics and Gynecology.