Major influencing factors identification and probabilistic health risk assessment of soil potentially toxic elements pollution in coal and metal mines across China: A systematic review.

Deposition of potentially toxic elements (PTEs) in soils due to different types of mining activities has been an increasingly important concern worldwide. Quantitative differences of soil PTEs contamination and related health risk among typical mines remain unclear. Herein, data from 110 coal mines and 168 metal mines across China were analyzed based on 265 published literatures to evaluate pollution characteristics, spatial distribution, and probabilistic health risks of soil PTEs. The results showed that PTE levels in soil from both mine types significantly exceeded background values. The geoaccumulation index (Igeo) revealed metal-mine soil pollution levels exceeded those of coal mines, with average Igeo values for Cd, Hg, As, Pb, Cu, and Zn being 3.02-15.60 times higher. Spearman correlation and redundancy analysis identified natural and anthropogenic factors affecting soil PTE contamination in both mine types. Mining activities posed a significant carcinogenic risk, with metal-mine soils showing a total carcinogenic risk an order of magnitude higher than in coal-mine soils. This study provides policymakers a quantitative foundation for developing differentiated strategies for sustainable remediation and risk-based management of PTEs in typical mining soils.

Statistical approaches to evaluate in vitro dissolution data against proposed dissolution specifications.

In vitro dissolution testing is a regulatory required critical quality measure for solid dose pharmaceutical drug products. Setting the acceptance criteria to meet compendial criteria is required for a product to be filed and approved for marketing. Statistical approaches for analyzing dissolution data, setting specifications and visualizing results could vary according to product requirements, company's practices, and scientific judgements. This paper provides a general description of the steps taken in the evaluation and setting of in vitro dissolution specifications at release and on stability.

Scorpion venom heat-resistant peptide alleviates mitochondrial dynamics imbalance induced by PM2.5 exposure by downregulating the PGC-1α/SIRT3 signaling pathway.

Background: Epidemiological inquiry reveals that neuroinflammation and mitochondrial dysfunction caused by PM2.5 exposure are associated with Alzheimer's disease. Nevertheless, the molecular mechanisms of mitochondrial dynamics and neuroinflammation induced by PM2.5 exposure remain elusive. In this study, our objective was to explore the impact of PM2.5 on mitochondrial dynamics and neuroinflammation, while also examining the reparative potential of scorpion venom heat-resistant synthetic peptide (SVHRSP). Methods: Western blot and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were employed to ascertain the protein and gene levels of IL-1ß, IL-6, and TNF-α in BV2 cells. The concentration of IL-6 in the supernatant of the BV2 cell culture was measured by enzyme-linked immunosorbent assay. For the assessment of mitochondrial homeostasis, western blot, RT-qPCR, and cellular immunohistochemistry methods were utilized to investigate the protein and gene levels of DRP1 and MFN-2 in HT22 cells. In the context of signal pathway analyses, western blot, RT-qPCR, and immunofluorescence techniques were employed to detect the protein and gene expressions of PGC-1α and SIRT3 in HT22 cells, respectively. Following the transfection with siPGC-1αRNA, downstream proteins of PGC-1α/SIRT3 pathway in HT22 cells were investigated by Western blot and RT-qPCR. Results: The experimental findings demonstrated that exposure to PM2.5 exacerbated neuroinflammation, resulting in elevated levels of IL-1ß, IL-6, and TNF-α. Furthermore, it perturbed mitochondrial dynamics, as evidenced by increased DRP1 expression and decreased MFN-2 expression. Additionally, dysfunction was observed in the PGC-1α/SIRT3 signal pathway. However, intervention with SVHRSP ameliorated the cellular damage induced by PM2.5 exposure. Conclusions: SVHRSP alleviated neuroinflammation and mitochondrial dynamics imbalance induced by PM2.5 exposure by downregulating the PGC-1α/SIRT3 signaling pathway.

A novel LC-MS/MS method combined with derivatization for simultaneous quantification of vitamin D metabolites in human serum with diabetes as well as hyperlipidemia.

Vitamin D plays an important role in calcium homeostasis. Recent studies indicate that vitamin D deficiency has become a major public health problem. In order to define vitamin D status, many analytical methods were used to quantify 25-hydroxyvitamin D (25OHD), as circulating 25OHD is regarded as the best indicator to evaluate vitamin D status. The current LC-MS/MS technology is internationally recognized as the "gold standard" for the detection of vitamin D and its metabolites. The impediment to the analysis of vitamin D metabolites is the low level of 25OHD and 1,25(OH)2D. Therefore, it is challenging to achieve the desired sensitivity and accuracy in the determination of trace vitamin D compounds in biological liquids. Here, a method based on liquid-liquid extraction in combination with derivatization, followed by liquid chromatography-electrospray/tandem mass spectrometry was developed for determination of the vitamin D metabolites, including 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D2 and 1α,25-dihydroxyvitamin D3. The method was simple and rapid, and it was validated with good linearity (R2 > 0.998), excellent recovery (average value with 81.66-110.31%) and high precision of intra-day and inter-day (0.06-6.38% and 0.20-6.82%). The values of limit of detection (LOD) and limit of quantitation (LOQ) were as low as 0.3 ng mL-1 and 1.0 ng mL-1, respectively. Finally, the developed method was successfully applied to determination of the vitamin D metabolites from the human serum samples of healthy subjects and patients with diabetes as well as hyperlipidemia.

Structural and mineralogical variation upon reoxidation of reduced Fe-bearing clay minerals during thermal activation.

The hydroxyl radicals (OH) produced from Fe(II) oxidation upon reoxidation of reduced Fe-bearing clay minerals (RFC) have received increased attention and thermal activation was used to enhance Fe(II) oxidation to improve OH production. However, changes in mineral morphology and structure during thermally-activated RFC reoxidation are not yet clear. Herein, the Fe(II) oxidation extent was measured by chemical analysis during the reoxidation of model RFC (reduced nontronite (rNAu-2) at elevated temperatures. Mineralogical variation of rNAu-2 particles was observed by scanning electron microscopy (SEM), Mössbauer spectra, and X-ray photoelectron spectroscopy (XPS). The structural Fe(II) oxidation in rNAu-2 was accelerated with increasing temperature, accompanied by the transformation of structural entities and the dissolution of Fe and Si, while the overall structure of rNAu-2 minerals was relatively intact. The surface microstructure of particles showed the dissolved holes, net-shape flocs, and even large pore channels after Fe(II) oxidation by thermal activation. Moreover, the rearrangement of structural Fe(II) entities, the regeneration of edge Fe(II), and the electron transport from the interior to the edge were enhanced during rNAu-2 reoxidation by thermal activation. The increasing electron transfer at elevated temperatures could possibly be owing to the increasing number of reactive sites by increasing the internal disorder of rNAu-2. This work provides novel insights into the structural and mineralogical changes in promoting electron transfer upon RFC reoxidation.

The importance of and difficulties involved in creating molecular probes for a carbon monoxide gasotransmitter.

As one of the triumvirate of recognized gasotransmitter molecules, namely NO, H2S, and CO, the physiological effects of CO and its potential as a biomarker have been widely investigated, garnering particular attention due to its reported hypotensive, anti-inflammatory, and cytoprotective properties, making it a promising therapeutic agent. However, the development of CO molecular probes has remained relatively stagnant in comparison with the fluorescent probes for NO and H2S, owing to its inert molecular state under physiological conditions. In this review, starting from elucidating the definition and significance of CO as a gasotransmitter, the imperative for the advancement of CO probes, especially fluorescent probes, is expounded. Subsequently, the current state of development of CO probe methodologies is comprehensively reviewed, with an overview of the challenges and prospects in this burgeoning field of research.

The Unique Genetic Mutation Characteristics Based on Large Panel Next-Generation Sequencing (NGS) Detection in Multiple Primary Lung Cancers (MPLC) Patients.

BACKGROUND: With the wide application of multislice spiral computed tomography (CT), the frequency of detection of multiple lung cancer is increasing. This study aimed to analyze gene mutations characteristics in multiple primary lung cancers (MPLC) using large panel next-generation sequencing (NGS) assays. METHODS: Patients with MPLC surgically removed from the Affiliated Hospital of Guangdong Medical University from Jan 2020 to Dec 2021 enrolled the study. NGS sequencing of large panels of 425 tumor-associated genes was performed. RESULTS: The 425 panel sequencing of 114 nodules in 36 patients showed that epidermal growth factor receptor (EGFR) accounted for the largest proportion (55.3%), followed by Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) (9.6%), v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), and Kirsten rat sarcoma viral oncogene (KRAS) (8.8%). Fusion target variation was rare (only 2, 1.8%). ERBB2 Y772_A775dup accounted for 73%, KRAS G12C for about 18%, and BRAF V600E for only 10%. AT-rich interaction domain 1A (ARID1A) mutations were significantly higher in invasive adenocarcinoma (IA) which contained solid/micro-papillary malignant components (p = 0.008). The tumor mutation burden (TMB) distribution was low, with a median TMB of 1.1 MUTS/Mb. There were no differences in the TMB distribution of different driver genes. In addition, 97.2% of MPLC patients (35/36) had driver gene mutations, and 47% had co-mutations, mainly in IA (45%) and invasive adenocarcinoma (MIA) (37%) nodule, with EGFR (39.4%), KRAS (9.1%), ERBB2 (6.1%), tumor protein 53 (TP53) (6.1%) predominately. CONCLUSIONS: MPLC has a unique genetic mutation characteristic that differs from advanced patients and usually presents with low TMB. Comprehensive NGS helps to diagnose MPLC and guides the MPLC clinical treatment. ARID1A is significantly enriched in IA nodules containing micro-papillary/solid components, suggesting that these MPLC patients may have a poor prognosis.

Risk Control Values and Remediation Goals for Benzo[a]pyrene in Contaminated Sites: Sectoral Characteristics, Temporal Trends, and Empirical Implications.

Benzo[a]pyrene (BaP) is a highly carcinogenic pollutant of global concern. There is a need for a comprehensive assessment of regulation decisions for BaP-contaminated site management. Herein, we present a quantitative evaluation of remediation decisions from 206 contaminated sites throughout China between 2011 and 2021 using the cumulative distribution function (CDF) and related statistical methodologies. Generally, remediation decisions seek to establish remediation goals (RGs) based on the risk control values (RCVs). Cumulative frequency distributions, followed non-normal S-curve, emerged multiple nonrandom clusters. These clusters are consistent with regulatory guidance values (RGVs), of national and local soil levels in China. Additionally, priority interventions for contaminated sites were determined by prioritizing RCVs and identifying differences across industrial sectors. Notably, we found that RCVs and RGs became more relaxed over time, effectively reducing conservation and unsustainable social and economic impacts. The joint probability curve was applied to model decision values, which afforded a generic empirically important RG of 0.57 mg/kg. Overall, these findings will help decision-makers and governments develop appropriate remediation strategies for BaP as a ubiquitous priority pollutant.

CircCDR1as mediates PM2.5-induced lung cancer progression by binding to SRSF1.

Research indicates that particulate matter with an aerodynamic equivalent diameter of less than or equal to 2.5 µm in ambient air may induce lung cancer progression. Circular RNAs are a special kind of endogenous noncoding RNA, and their functions are reflected in various diseases and physiological processes, but there are still few studies related to PM2.5-induced lung cancer. Here, we identified that circCDR1as was upregulated in lung cancer cells stimulated with PM2.5 and positively correlated with the malignant features of lung cancer. The lower expression of CircCDR1as reduced the adverse progression of lung cancer cells after PM2.5 treatment; the lower expression of circCDR1as impaired the growth size and metastatic ability of lung cancer cells in mouse tumour models. Mechanistically, circCDR1as specifically bound to serine/arginine-rich splicing Factor 1 (SRSF1) and affected the splicing of vascular endothelial growth factor-A (VEGFA) by SRSF1. Furthermore, circCDR1as affected SRSF1 function by regulating PARK2-mediated SRSF1 ubiquitination, protein production and degradation. CircCDR1as also affected C-myc and cyclin D1 expression by regulating SRSF1 and affecting the wnt/ß-catenin signalling pathway, ultimately promoting malignant behavior and inhibiting the apoptosis of lung cancer cells, thereby causing PM2.5-induced lung cancer development.

Insights into the degradation process of phenol during in-situ thermal desorption: The overlooked oxidation of hydroxyl radicals from oxygenation of reduced Fe-bearing clay minerals.

In-situ thermal desorption (ISTD) has attracted increasing attention owing to the efficient removal of organic contaminants from contaminated sites. However, it is poorly understood that whether and to what extent contamination degradation occurs upon oxygenation of reduced Fe-bearing clay minerals (RFC) in the subsurface during ISTD. In this study, we evaluated the mechanism of contaminant degradation upon oxygenation of reduced clay minerals during the ISTD. Reduced nontronite (rNAu-2) and montmorillonite (rSWy-3) were selected as RFC models. Results showed that thermal treatment during ISTD could significantly enhance phenol degradation, which increased from 25.8 % at 10 °C to 74.4 % at 70 °C in rNAu-2 and from 17.7 % at 10 °C to 49.8 % at 70 °C in rSWy-3. Correspondingly, the cumulative •OH at steady-state ([•OH]ss) increased by 3.7 and 1.5 times, respectively. The acceleration of Fe(II) oxidation with increasing temperature could be mainly responsible for [•OH]ss generation, which degrades phenol. Moreover, thermal treatment improved the fast oxidation of trioctahedral entities Fe(II)Fe(II)Fe(II) (TOF) and the slow oxidation of dioctahedral entities Fe(II)Fe(II) (DTF1), AlFe(II) (DAF1), and Fe(II)Fe(III) (DTF2). Our study suggests that the overlooked degradation progress of phenol by oxygenation of RFC during ISTD, and it could be favorable for contaminant degradation during remediation.

Leaching Characteristics of Heavy Metals in the Baghouse Filter Dust from Direct-Fired Thermal Desorption of Contaminated Soil.

After thermal desorption, the total amount of heavy metals (HMs) is enriched in baghouse filter dust. To further understand the related environmental impact, the leaching characteristics under various conditions must be explored. Therefore, this study aimed to examine the leaching characteristics of seven HMs in the dust generated in the direct-fired thermal desorption process and to compare the differences in heavy metal leaching characteristics in the soil before and after thermal desorption. The leaching characteristics and bioaccessibility of seven HMs-arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), lead (Pb), nickel (Ni), and zinc (Zn)-were analyzed in dust and in soil before and after thermal desorption. The activity of HMs in dust was strong. Therefore, environmental effects and effects on human health should be considered in the treatment of soil and dust after thermal desorption.

Combining autophagy and immune characterizations to predict prognosis and therapeutic response in lung adenocarcinoma.

Background: Autophagy, a key regulator of programmed cell death, is critical for maintaining the stability of the intracellular environment. Increasing evidence has revealed the clinical importance of interactions between autophagy and immune status in lung adenocarcinoma. The present study evaluated the potential of autophagy-immune-derived biomarkers to predict prognosis and therapeutic response in patients with lung adenocarcinoma. Methods: Patients from the GSE72094 dataset were randomized 7:3 to a training set and an internal validation set. Three independent cohorts, TCGA, GSE31210, and GSE37745, were used for external verification. Unsupervised hierarchical clustering based on autophagy- and immune-associated genes was used to identify autophagy- and immune-associated molecular patterns, respectively. Significantly prognostic autophagy-immune genes were identified by LASSO analysis and by univariate and multivariate Cox regression analyses. Differences in tumor immune microenvironments, functional pathways, and potential therapeutic responses were investigated to differentiate high-risk and low-risk groups. Results: High autophagy status and high immune status were associated with improved overall survival. Autophagy and immune subtypes were merged into a two-dimensional index to characterize the combined prognostic classifier, with 535 genes defined as autophagy-immune-related differentially expressed genes (DEGs). Four genes (C4BPA, CD300LG, CD96, and S100P) were identified to construct an autophagy-immune-related prognostic risk model. Survival and receiver operating characteristic (ROC) curve analyses showed that this model was significantly prognostic of survival. Patterns of autophagy and immune genes differed in low- and high-risk patients. Enrichment of most immune infiltrating cells was greater, and the expression of crucial immune checkpoint molecules was higher, in the low-risk group. TIDE and immunotherapy clinical cohort analysis predicted that the low-risk group had more potential responders to immunotherapy. GO, KEGG, and GSEA function analysis identified immune- and autophagy-related pathways. Autophagy inducers were observed in patients in the low-risk group, whereas the high-risk group was sensitive to autophagy inhibitors. The expression of the four genes was assessed in clinical specimens and cell lines. Conclusions: The autophagy-immune-based gene signature represents a promising tool for risk stratification in patients with lung adenocarcinoma, guiding individualized targeted therapy or immunotherapy.

Vascular Disruptive Hydrogel Platform for Enhanced Chemotherapy and Anti-Angiogenesis through Alleviation of Immune Surveillance.

Patients undergoing immunotherapy always exhibit a low-response rate due to tumor heterogeneity and immune surveillance in the tumor. Angiogenesis plays an important role in affecting the status of tumor-infiltrated lymphocytes by inducing hypoxia and acidosis microenvironment, suggesting its synergistic potential in immunotherapy. However, the antitumor efficacy of singular anti-angiogenesis therapy often suffers from failure in the clinic due to the compensatory pro-angiogenesis signaling pathway. In this work, classic injectable thermosensitive PLGA-PEG-PLGA copolymer was used to construct a platform to co-deliver CA4P (vascular disruptive agent) and EPI for inducing immunogenic cell death of cancer cells by targeting the tumor immune microenvironment. Investigation of 4T1 tumor-bearing mouse models suggests that local administration of injectable V+E@Gel could significantly inhibit the proliferation of cancer cells and prolong the survival rate of 4T1 tumor-bearing mouse models. Histological analysis further indicates that V+E@Gel could effectively inhibit tumor angiogenesis and metastasis by down-regulating the expression of CD34, CD31, MTA1 and TGF-ß. Moreover, due to the sustained release kinetics of V+E@Gel, its local administration relieves the immune surveillance in tumor tissues and thus induces a robust and long-lasting specific antitumor immune response. Overall, this work provides a new treatment strategy through the mediation of the tumor immune microenvironment by vascular disruption to fulfill enhanced chemotherapy and immunotherapy.

PM2.5 induced lung injury through upregulating ROS-dependent NLRP3 Inflammasome-Mediated Pyroptosis.

The main cause of air pollution is PM2.5, which directly causes lung injury through respiration. Oxidative stress and inflammation are considered to be the key mechanism of cell damage. Pyroptosis is a process of the programmed death of inflammatory cells and as a dangerous endogenous signal, it is widely involved in different inflammatory diseases. However, few studies have been conducted on PM2.5 exposure and cell pyroptosis. In this study, we aimed to investigate the effect of PM2.5 on apoptosis, pyroptosis and cell cycle arrest regulated by reactive oxygen species production. Balb/c mice were exposed to PM2.5 dynamically and verified by the RAW264.7 cells in vitro. The results showed the activation of NF-κB and NLRP3 inflammasome and the release of IL-1ß and reactive oxygen species were caused by exposure to PM2.5. The maturation of IL-1ß relied on Caspase-1, and the active Caspase-1 was related to cell pyroptosis. Oxidative stress, inflammation, apoptosis and pyroptosis all affected the cell cycle. This study describes a potentially important mechanism of PM2.5-induced lung damage that PM2.5 promotes lung injury via upregulating ROS-NLRP3-mediated the RAW264.7 cells pyroptosis.

Remarkable enrichment of heavy metals in baghouse filter dust during direct-fired thermal desorption of contaminated soil.

This study focuses on the widely applied technology of direct-fired thermal desorption, taking a site contaminated by polycyclic aromatic hydrocarbons (PAHs) as a typical test case. The entire thermal desorption process of contaminated soil is considered in the analysis. The concentration levels and occurrence characteristics of heavy metals in dust traditionally considered to be clean are evaluated, and possible secondary pollution and environmental impacts are explored. The results indicate that, compared with the thermal desorption soil, the dust samples generated in the baghouse filter during the ex situ direct-fired thermal desorption process have higher amounts of heavy metal accumulation as well as altered speciation. In addition, the enrichment characteristics and origins of the heavy metals are analyzed according to the process flow and particle size composition as well as the results of X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), electron probe microanalysis (EPMA), and other microscopic research methods. Phenomenon further reveals enrichment of arsenic (As), nickel (Ni), and chromium (Cr). The findings of this study can provide a scientific basis for the proper disposal and risk management of the dust collected after direct-fired thermal desorption treatment of contaminated soil.

Chemodiversity of dissolved organic matter in cadmium-contaminated paddy soil amended with different materials.

Dissolved organic matter (DOM) in soil is a key factor affecting the bioavailability of heavy metals, but very few studies have focused on the role of DOM in the use of soil amendments to mitigate heavy metal accumulation in crops. Here, eleven materials were added to cadmium (Cd)-contaminated paddy soil in greenhouse pot trials; rice was grown and harvested, the chemodiversity of post-harvest soil DOM was characterized using Fourier-Transform Ion Cyclotron Resonance Mass Spectrometry, and the specific associations between soil DOM traits and water-extractable soil Cd concentration were identified at the molecular level. The results showed that the endogenous release caused by altering soil pH had a greater effect on soil DOM concentration than did the exogenous chemical input due to the application of organic amendments, which in turn contributed to the chemodiversity of DOM. After one season of rice cultivation, soil DOM molecules were mainly dominated by relatively low molecular weight heteroatom-free lignins. C/N, C/H ratios of organic materials influenced DOM molecular fingerprint patterns, and soil pH and redox potential were the main driving forces affecting the chemodiversity of DOM. Furthermore, the low molecular weight, high saturation, low aromaticity, and heteroatom-free DOM molecules are more likely to dissolve Cd from the soil solid phase, thus increasing the potential risk of Cd to the environment. The results provide critical information about amendments-induced changes in DOM chemodiversity and will inform the selection of appropriate soil amendments.

Cement kiln co-processing promotes the redevelopment of industrially contaminated land in China: Spatio-temporal features and efficiency analysis.

The cleanup and redevelopment of industrially contaminated land are essential for sustainable urban development, both from economic and environmental perspectives. Remediation efforts in developed countries have incurred high decontamination costs and administrative, monitoring, and enforcement requirements that are beyond the capabilities of many developing nations. Here, we reviewed the development of cement kiln co-processing of contaminated soils, a commonly used remediation strategy in China, and discussed the spatio-temporal features, benefits and efficiency of co-processing. Our results show that urbanization, the real estate market, and policies have impacts on the development of technology. By June 2021, cement kiln co-processing has disposed of approximately 2,633, 823 m3 of contaminated soils, and the average feed rates of organic pollutants, combined pollution, and heavy metals are 6%, 4%, and 3%, respectively. The average cost of co-processing contaminated soil is US$167.2 per cubic meter, which is lower than that of other conventional remedies. Based on the pollution status and cement production capacity, it is most likely that the co-processing strategy will be adopted by three countries of India, Indonesia, and Vietnam in the next few years. In the future, more data will be needed to quantify and assess the technology diffusion at the provincial level and the technological details of adopting this strategy.

Identification of Prognostic Model Based on Immune-Related LncRNAs in Stage I-III Non-Small Cell Lung Cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) participate in the regulation of immune response and carcinogenesis, shaping tumor immune microenvironment, which could be utilized in the construction of prognostic signatures for non-small cell lung cancer (NSCLC) as supplements. METHODS: Data of patients with stage I-III NSCLC was downloaded from online databases. The least absolute shrinkage and selection operator was used to construct a lncRNA-based prognostic model. Differences in tumor immune microenvironments and pathways were explored for high-risk and low-risk groups, stratified by the model. We explored the potential association between the model and immunotherapy by the tumor immune dysfunction and exclusion algorithm. RESULTS: Our study extracted 15 immune-related lncRNAs to construct a prognostic model. Survival analysis suggested better survival probability in low-risk group in training and validation cohorts. The combination of tumor, node, and metastasis staging systems with immune-related lncRNA signatures presented higher prognostic efficacy than tumor, node, and metastasis staging systems. Single sample gene set enrichment analysis showed higher infiltration abundance in the low-risk group, including B cells (p<0.001), activated CD8+ T cells (p<0.01), CD4+ T cells (p<0.001), activated dendritic cells (p<0.01), and CD56+ Natural killer cells (p<0.01). Low-risk patients had significantly higher immune scores and estimated scores from the ESTIMATE algorithm. The predicted proportion of responders to immunotherapy was higher in the low-risk group. Critical pathways in the model were enriched in immune response and cytoskeleton. CONCLUSIONS: Our immune-related lncRNA model could describe the immune contexture of tumor microenvironments and facilitate clinical therapeutic strategies by improving the prognostic efficacy of traditional tumor staging systems.

KEAP1/NFE2L2 Mutations of Liquid Biopsy as Prognostic Biomarkers in Patients With Advanced Non-Small Cell Lung Cancer: Results From Two Multicenter, Randomized Clinical Trials.

PURPOSE: The KEAP1-NFE2L2 (Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)) mutations are associated with resistance to chemotherapy or immunotherapy in non-small cell lung cancer (NSCLC). Conversely, it has been reported that NFE2L2 mutations potentiate improved clinical outcome with immunotherapy. However, therapeutic benefits for patients with KEAP1/NFE2L2 mutations remain unclear. The purpose of this study was to investigate the association between KEAP1/NFE2L2 and NSCLC prognosis, and to explore whether immunotherapy can improve prognosis in populations with KEAP1/NFE2L2 mutations. EXPERIMENTAL DESIGN: The impact of KEAP1/NFE2L2 mutations on survival outcomes in NSCLC patients received immunotherapy and chemotherapy was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, POPLAR (n = 211) and OAK (n = 642)). The Cancer Genome Atlas (TCGA) NSCLC cohort (n=998) and an in-house Chinese NSCLC cohort (n=733) was used For the analysis of immune-related markers. RESULTS: Compared with KEAP1/NFE2L2 wild-type, patients with KEAP1/NFE2L2 mutations were significantly associated with poorer overall survival (OS, HR = 1.97, 95% CI 1.48-2.63, P < 0.001) on atezolizumab and docetaxel (HR = 1.66, 95% CI 1.28-2.16, P < 0.001). In KEAP1/NFE2L2 mutant group, there was no significant difference in median OS between atezolizumab and docetaxel (HR 0.74, 95% CI 0.53-1.03, P = 0.07). NFE2L2/KEAP1 mutations were significantly associated with higher TMB values and PD-L1 expression in the OAK/POPLAR and in-house Chinese NSCLC cohorts. GSEA revealed that KEAP1/NFE2L2mutant subgroup was associated with deficient infiltration of CD4+ T cells, NK T cells and natural Treg cells, and lower expression of DNA damage response genes in TCGA NSCLC cohort. CONCLUSIONS: Our study revealed that patients with KEAP1/NFE2L2 mutations have a worse prognosis than wild-type patients, both on immunotherapy and chemotherapy. In addition, in patients with KEAP1/NFE2L2 mutations, immunotherapy did not significantly improve prognosis compared to chemotherapy.

Compound essential oils relieve oxidative stress caused by PM2 .5 exposure by inhibiting autophagy through the AMPK/mTOR pathway.

Fine particulate matter (PM2.5 ) potentially damages the respiratory system and causes respiratory diseases. Compound essential oils (CEOs) have been shown to alleviate the damage to the lung and macrophages caused by PM2.5 . However, the effect of PM2.5 exposure on the brain has rarely been investigated. When oxidative stress occurs in the brain, it readily causes neurological diseases. Autophagy is intimately involved in many physiological processes, especially processes important for the brain. Blocked or excessive autophagy causes a series of brain diseases, such as cerebral ischemia and stroke. This study investigated whether CEOs regulate excessive autophagy and reduce the oxidative stress caused by PM2.5 in the brain and BV2 microglial cells. PM2.5 increased the levels of ROS, Nox2, NF-κB and MDA while decreasing superoxide dismutase and HO-1 levels, which led to oxidative stress in the brain. The increased LC3 level and decreased P62 level suggested that PM2.5 exposure increased the level of autophagy. After exposure to PM2.5 , the levels of 5'-adenosine monophosphate-activated protein kinase (AMPK) increased, while the levels of mammalian target of rapamycin (mTOR) decreased, suggesting that PM2.5 might induce autophagy by activating the AMPK/mTOR pathway. In addition, CEOs alleviated oxidative stress and autophagy induced by PM2.5 . Therefore, we concluded that CEOs reduce oxidative stress induced by PM2.5 exposure by inhibiting autophagy via the AMPK/mTOR signaling pathway, and these findings provide new opportunities for the prevention of PM2.5 -induced brain diseases.