Distribution, risk evaluation, and source allocation of cesium and strontium in surface soil in a mining city.

Radioactive nuclides cesium (Cs) and strontium (Sr) possess long half-lives, with 135Cs at approximately 2.3 million years and 87Sr at about 49 billion years. Their persistent accumulation can result in long-lasting radioactive contamination of soil ecosystems. This study employed geo-accumulation index (Igeo), pollution load index (PLI), potential ecological risk index (PEPI), health risk assessment model (HRA), and Monte Carlo simulation to evaluate the pollution and health risks of Cs and Sr in the surface soil of different functional areas in a typical mining city in China. Positive matrix factorization (PMF) model was used to elucidate the potential sources of Cs and Sr and the respective contribution rates of natural and anthropogenic sources. The findings indicate that soils in the mining area exhibited significantly higher levels of Cs and Sr pollution compared to smelting factory area, agricultural area, and urban residential area. Strontium did not pose a potential ecological risk in any studied functional area. The non-carcinogenic health risk of Sr to the human body in the study area was relatively low. Because of the lack of parameters for Cs, the potential ecological and human health risks of Cs was not calculated. The primary source of Cs in the soil was identified as the parent material from which the soil developed, while Sr mainly originated from associated contamination caused by mining activities. This research provides data for the control of Cs and Sr pollution in the surface soil of mining city.

The role of LncRNA-mediated autophagy in cancer progression.

Long non-coding RNAs (lncRNAs) are a sort of transcripts that are more than 200 nucleotides in length. In recent years, many studies have revealed the modulatory role of lncRNAs in cancer. Typically, lncRNAs are linked to a variety of essential events, such as apoptosis, cellular proliferation, and the invasion of malignant cells. Simultaneously, autophagy, an essential intracellular degradation mechanism in eukaryotic cells, is activated to respond to multiple stressful circumstances, for example, nutrient scarcity, accumulation of abnormal proteins, and organelle damage. Autophagy plays both suppressive and promoting roles in cancer. Increasingly, studies have unveiled how dysregulated lncRNAs expression can disrupt autophagic balance, thereby contributing to cancer progression. Consequently, exploring the interplay between lncRNAs and autophagy holds promising implications for clinical research. In this manuscript, we methodically compiled the advances in the molecular mechanisms of lncRNAs and autophagy and briefly summarized the implications of the lncRNA-mediated autophagy axis.

Systematic biases in reference-based plasma cell-free DNA fragmentomic profiling.

Plasma cell-free DNA (cfDNA) fragmentation patterns are emerging directions in cancer liquid biopsy with high translational significance. Conventionally, the cfDNA sequencing reads are aligned to a reference genome to extract their fragmentomic features. In this study, through cfDNA fragmentomics profiling using different reference genomes on the same datasets in parallel, we report systematic biases in such conventional reference-based approaches. The biases in cfDNA fragmentomic features vary among races in a sample-dependent manner and therefore might adversely affect the performances of cancer diagnosis assays across multiple clinical centers. In addition, to circumvent the analytical biases, we develop Freefly, a reference-free approach for cfDNA fragmentomics profiling. Freefly runs ∼60-fold faster than the conventional reference-based approach while generating highly consistent results. Moreover, cfDNA fragmentomic features reported by Freefly can be directly used for cancer diagnosis. Hence, Freefly possesses translational merit toward the rapid and unbiased measurement of cfDNA fragmentomics.

The rheumatoid arthritis drug auranofin exerts potent anti-lymphoma effect by stimulating TXNRD-mediated ROS generation and inhibition of energy metabolism.

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity.

Generalizable transcriptome-based tumor malignant level evaluation and molecular subtyping towards precision oncology.

In cancer treatment, therapeutic strategies that integrate tumor-specific characteristics (i.e., precision oncology) are widely implemented to provide clinical benefits for cancer patients. Here, through in-depth integration of tumor transcriptome and patients' prognoses across cancers, we investigated dysregulated and prognosis-associated genes and catalogued such important genes in a cancer type-dependent manner. Utilizing the expression matrices of these genes, we built models to quantitatively evaluate the malignant levels of tumors across cancers, which could add value to the clinical staging system for improved prediction of patients' survival. Furthermore, we performed a transcriptome-based molecular subtyping on hepatocellular carcinoma, which revealed three subtypes with significantly diversified clinical outcomes, mutation landscapes, immune microenvironment, and dysregulated pathways. As tumor transcriptome was commonly profiled in clinical practice with low experimental complexity and cost, this work proposed easy-to-perform approaches for practical clinical promotion towards better healthcare and precision oncology of cancer patients.

Identification of TAP1 as a T-cell related therapeutic target in gastric cancer by mediating oxalipliatin-related synergistic enhancement of immunotherapy.

BACKGROUND: Given the intricate molecular complexities and heterogeneity inherent in T-cell immunotherapy of gastric cancer (GC), elucidative T-cell-related biomarkers were imperative needed for facilitating the prediction of GC patient prognosis and identify potential synergistic therapeutic targets. METHODS: We conducted COX regression analysis in TISIDB, TCGA-STAD, and GEO databases to identify 19 GC T-cell-mediated sensitivity tumor killing (TTK) genes (key GCTTKs). Based on key GCTTKs, we constructed two TTK patterns and analyzed their metabolic pathways, mutation features, clinical data distribution, immune cell infiltration, and prognosis. LASSO regression was performed to develop a T-cell-mediated GC Prognosis (TGCP) model. We validated the TGCP model in GC patients. TAP1 was further selected for investigation of its biological functions and molecular mechanisms. We assessed the potential of TAP1 as a promising therapeutic target for GC using Patient-derived organoids (PDOs)-derived xenografts (PDOXs) models of GC. RESULTS: The TTK patterns display notable disparities. The TGCP model showcases its proficiency in predicting immune response efficacy, effectively distinguishes immunotherapy difference GC patients. Our findings find further confirmation in PDOX models, affirming TAP1 can enhance immunotherapy facilitated by PDL1 inhibitors. Furthermore, Oxaliplatin, by promoting TAP1 expression, augments PDL1 expression, thereby enhancing the efficacy of immunotherapy. CONCLUSIONS: We constructed a TGCP model, which demonstrates satisfactory predictive accuracy. Out of 9 prognostic genes, TAP1 was validated as a synergistic target for Oxaliplatin and PDL1 inhibitors, offering a genetic-level explanation for the synergy observed in GC treatment involving Oxaliplatin in combination with PDL1 inhibitors.

Linker Histone H1.4 Inhibits the Growth, Migration and EMT Process of Non-Small Cell Lung Cancer by Regulating ERK1/2 Expression.

H1.4 is one of the 11 variants of linker histone H1, and is associated with tumorigenesis and development of various cancers. However, it is unclear for the role of histone H1.4 in non-small cell lung cancer (NSCLC). In this study, we found that overexpression of H1.4 significantly inhibited the cell viability, migration, invasion and epithelial-mesenchymal transition (EMT) processes, whereas silencing H1.4 by shRNA knockdown promoted these processes in NSCLC cell lines A549 and H1299. We further showed that H1.4 overexpression reduced ERK1/2 expression or its phosphorylation levels, while H1.4 knockdown increased ERK1/2 expression or phosphorylation levels in NSCLC. Furthermore, we demonstrated that H1.4 bound to the promoter of ERK1/2, and acted as a transcriptional suppressor to inhibit ERK1/2 expression in A549 or H1299 cells. Importantly, we found that ERK ecto-expression can largely recovered the inhibitory effects of H1.4 on cell viability, migration, invasion and EMT processes. In summary, our study reveals that the H1.4-ERK pathway is crucial for cell viability, migration, invasion and EMT of NSCLC and could be a therapeutic target for NSCLC.

H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis.

The role of the Immunoglobulin Superfamily (IgSF) as adhesion molecules in orchestrating inflammation is pivotal, yet its specific involvement in gastric cancer (GC) remains unknown. We analyzed IgSF components and discerned conspicuously elevated VCAM1 expression in GC, correlating with a poor prognosis. Remarkably, VCAM1 enhances GC cell proliferation and migration by activating AKT-mTOR signaling. Moreover, lactate in the tumor microenvironment (TME) promotes dynamic lactylation of H3K18 (H3K18la), leading to transcriptional activation of VCAM1 in GC cells. Furthermore, VCAM1 actively mediates intercellular communication in the TME. AKT-mTOR-mediated CXCL1 expression is increased by VCAM1, facilitating the recruitment of human GC-derived mesenchymal stem cells (hGC-MSCs), thereby fostering immunesuppression and accelerating cancer progression. In summary, H3K18 lactylation upregulated VCAM1 transcription, which activated AKT-mTOR signaling, and promoted tumor cell proliferation, EMT Transition and tumor metastasis. VCAM1 upregulated CXCL1 expression by AKT-mTOR pathway, so as to facilitate hGC-MSCs and M2 macrophage recruitment and infiltration. These findings provide novel therapeutic targets for GC.

Proposals for the delineation of neck clinical target volume for definitive Radiation therapy in patients with oral/ oropharyngeal squamous cell cancer based on lymph node distribution.

PURPOSE/OBJECTIVE(S): To establish the distribution pattern of cervical lymph node metastasis (LNM) and propose optimized clinical target volume (CTV) boundaries specific to oral/ oropharyngeal squamous cell cancer (OSCC/OPSCC). MATERIALS/METHODS: 531 patients with pathologically confirmed OSCC/OPSCC were enrolled from January 2013 to June 2022. Patients were stratified into two groups based on the minimal distance from the lesion's edge to the body's midline: ≤1 cm or > 1 cm. The geometric center of cervical metastatic LN was marked on a template CT. LN distribution probability maps were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to OSCC/OPSCC. RESULTS: A total of 1962 positive LNs were enrolled. Compared with the > 1 cm group, the ≤ 1 cm group has following feature tendencies: male smokers, younger, median organs, large gross lesion, infiltrative growth pattern, contralateral LNM. The most frequently involved level of LNM was ipsilateral II, but ipsilateral Ib had the highest involvement rate in the > 1 cm OSCC group. In addition, tongue cancer had a higher incidence of LN extranodal extension (ENE), which mainly distributes in ipsilateral level II. The skip metastasis was prone to from level III to Vb (3.5 %) in LN(+)/ENE (-), and level Ib to VIa (3.7 %) in LN(+)/ENE (+). Accordingly, we proposed the following modifications: 1. only including lateral and posterior margin of submandibular gland within 5 mm; 2. retracting posterior boundary of level II to front edge of levator scapula muscle, and descending the upper boundary to transverse process of C2 vertebra only for OSCC; 3. including posterior third of thyroglossal muscle or anterior edge of sternocleidomastoid muscle; 4. sparing level Va in case of only level II involvement; 5. including upper area of the thyroid cartilage plate in case of level Ib LN(+)/ENE (+); 6. sparing level VIIa is considered. CONCLUSION: This is the first description of LN topographic spread patterns for OSCC/OPSCC. Modified CTV for prophylactic irradiation was proposed to spare the organs at risk and minimize adverse effects.

Molecular mechanism of honeysuckle + forsythia in treatment of acute lung injury based on network pharmacology.

The pathogenesis of acute lung injury (ALI) is complex and it is a common critical illness in clinical practice, seriously threatening the lives of critically ill patients, for which no specific molecular marker exists and there is a lack of effective methods for the treatment of ALI. The present study aimed to investigate the mechanism of action of honeysuckle and forsythia in treatment of acute lung injury (ALI) based on network pharmacology and in vitro modeling. The active ingredients and targets of honeysuckle and forsythia were predicted using traditional Chinese medicine systems pharmacology, PubChem and Swiss Target Prediction databases, and the Cytoscape 3.7.2 software was used to construct a drug-component-potential target network. The potential targets were imported into the Search tool for recurring instances of neighboring genes) database to obtain protein-protein interactions and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Targets analysis using Database for Annotation, Visualization, and Integrated Discovery. AutoDock Vina 1.1.2 software was used for docking between key active ingredients and the target proteins to analyze the binding ability of the active ingredients to the primary targets in honeysuckle and forsythia. A total of 64 male BALB/c mice were randomly divided into control, model, positive drug (Lianhua-Qingwen capsule), honeysuckle, forsythia, honeysuckle + forsythia high-, medium- and low-dose groups. Lipopolysaccharide (LPS) was used to induced an ALI model. The lung tissues of the mice were stained with hematoxylin-eosin and the serum levels of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured 4 h after the LPS administration. Reverse transcription-quantitative PCR and western blotting were used to detect NF-κB mRNA and protein expression, respectively. Active ingredients of honeysuckle and forsythia acted on 265 common targets in ALI, which regulated NF-κB, tumor necrosis factor-α (TNF-α) and PI3K-AKT signaling pathway, HIF-1 signalling pathway to slow the inflammatory response in treatment of ALI. In the positive drug group, honeysuckle, forsythia group, honeysuckle + forsythia high-, medium- and low-dose groups, lung tissue damage were significantly decrease compared with the model group, and inflammatory cell infiltration was reduced. Compared with the model group, honeysuckle + forsythia groups experienced decreased damage caused by the LPS and inflammation in the lung tissues and significantly decreased TNF-α and NF-κB and MDA concentration and significantly increased the SOD and GSH-Px activities. The mechanism of the effect of honeysuckle and forsythia on ALI may be mediated by inhibition of TNF-α and NF-κB expression and the activation of antioxidant mechanisms to decrease production of pro-inflammatory cytokines in lung tissue, thus treating ALI.

Vanadium extraction from steel slag: Generation, recycling and management.

The metal vanadium has superior physical and chemical properties and has a wide range of applications in many fields of modern industry. The increasing demand for vanadium worldwide has led to the need to guarantee sustainable vanadium production. The smelting process of vanadium and titanium magnetite produces vanadium-bearing steel slag, a key material for vanadium extraction. Herein, vanadium production, consumption, and steel slag properties are discussed. A detailed review of methods for extracting vanadium from vanadium-bearing steel slag is presented, including the most commonly used roasting and leaching method, and direct leaching, bioleaching and enhanced leaching methods are also described. Finally, the rules and regulations of steel slag management are introduced. In general, it is necessary to further develop environmentally friendly vanadium extraction methods and technologies from vanadium containing solid wastes. This study provides research directions for the technology of vanadium extraction from steel slag.

Eosinophil dynamics during chemo-radiotherapy correlate to clinical outcome in stage â ¡-â £a nasopharyngeal carcinoma patients: Results from a large cohort study.

BACKGROUND AND PURPOSE: We investigated the dynamics of eosinophil depletion during definitive concurrent chemo-radiotherapy (CCRT) and their association with the prognosis of stage Ⅱ-Ⅳa nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Fuzzy C-means algorithm (FCMA) assessed longitudinal trends in circulating eosinophil counts (CECs) of 1225 patients throughout the period of radical radiotherapy. The prognostic impact on patients' survival was evaluated with Kaplan-Meier analysis and Cox proportional risk model was used to determine the hazard ratio for adverse prognostic effects in grades of eosinophil depletion. The interactive effect of pre-treatment CECs and CCRT on outcomes was evaluated using HRs within the framework of Cox regression models. RESULTS: Three grades of eosinophil depletion, as defined by the interaction between dynamic types of CECs in the period of treatment and the value of CECs at the termination of treatment, significantly stratified the poor prognosis in terms of progression-free survival (PFS), overall survival (OS), and distant metastasis-free survival (DMFS) [1.57-fold (P = 0.001), 1.69-fold (P = 0.007), and 1.51-fold (P = 0.019) for G1, 2.4-fold (P < 0.001), 2.76-fold (P < 0.001), and 2.31-fold (P < 0.001) for G2, as compared with G0]. Furthermore, high levels of pre-treatment CECs acted as the strongest protective factor against severe depletion grade (G0 vs. G2, HR = 0.20, P = 0.005; G1 vs. G2, HR = 0.14, P < 0.001). However, compared with radiotherapy alone, the benefit from CCRT was attenuated in patients with high pre-treatment CECs. CONCLUSIONS: CECs reduction after treatment in patients with NPC may be helpful in the clinical setting to aid in assessing the prognosis for standard treatment of NPC.

Research on the improvement effect of Saposhnikovia divaricata (Trucz.) Schischk on rheumatoid arthritis based on the "component-target-pathway" association.

OBJECTIVE: To investigate the therapeutic effect and mechanism of the traditional Chinese medicine Saposhnikovia divaricata (Trucz.) Schischk in rats with complete Freund's adjuvant-induced rheumatoid arthritis (RA). METHODS: The chemical targets and RA targets of Saposhnikovia divaricata (Trucz.) Schischk were acquired by the network pharmacological method. The complete Freund's adjuvant-induced rat RA model was used to further explore the mechanism of Saposhnikovia divaricata (Trucz.) Schischk in improving RA. Pathological changes in the volume of toes, body weight and synovial tissues of joints as well as serum inflammatory factor levels before and after the intervention of Saposhnikovia divaricata (Trucz.) Schischk were investigated. The key metabolic pathways were screened by correlations between metabolites and key targets. Finally, a quantitative analysis of key targets and metabolites was experimentally validated. RESULTS: Saposhnikovia divaricata (Trucz.) Schischk administration increased body weight, mitigated foot swelling and downregulated inflammatory cytokine levels in model rats. The histopathology showed that treatment with Saposhnikovia divaricata (Trucz.) Schischk can induce inflammatory cell infiltration and synovial hyperplasia and obviously reduce cartilage injuries, thus improving arthritis symptoms in rats. According to the network pharmacology-metabonomics association analysis results, the purine metabolic signaling pathway might be the key pathway for RA intervention with Saposhnikovia divaricata (Trucz.) Schischk. Targeted metabonomics, Western blotting (WB) and reverse transcription-polymerase chain reaction (RT‒PCR) assays showed that the recombinant adenosine deaminase (ADA) mRNA expression level and metabolic level of inosine in Saposhnikovia divaricata (Trucz.) Schischk administration group were lower than those of the model group. This reflected that Saposhnikovia divaricata (Trucz.) Schischk could improve RA by downregulating ADA mRNA expression levels and the metabolic level of inosine in the purine signaling pathway. CONCLUSION: Based on the "component-disease-target" association analysis, this study concludes that Saposhnikovia divaricata (Trucz.) Schischk improves complete Freund's adjuvant-induced RA symptoms in rats mainly by downregulating ADA mRNA expression levels in the purine metabolic signaling pathway, mitigating foot swelling, improving the levels of serum inflammatory factors (IL-1ß, IL-6 and TNF-α), and decreasing the ADA protein expression level to intervene in purine metabolism.

Effects of sodium tanshinone IIA sulfonate injection on inflammatory factors and vascular endothelial function in patients with acute coronary syndrome undergoing percutaneous coronary intervention: A systematic review and meta-analysis of randomized clinical trials.

Background: Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) therapy may experience further damage to the vascular endothelium, leading to increased inflammatory response and in-stent thrombosis. In many clinical studies, sodium tanshinone IIA sulfonate injection (STS) has been found to reduce inflammatory factors and enhance vascular endothelial function in patients with ACS while improving the prognosis of PCI. However, to date, there has been no systematic review assessing the effectiveness and safety of STS on inflammatory factors and vascular endothelial function. Purpose: The aim of this study is to systematically review the effects of STS on inflammatory factors and endothelial function in patients with ACS treated with PCI. Methods: Until October 2022, eight literature databases and two clinical trial registries were searched for randomized controlled trials (RCTs) investigating STS treatment for ACS patients undergoing PCI. The quality of the included studies was assessed using the Cochrane Risk Assessment Tool 2.0. Meta-analysis was performed using RevMan 5.4 software. Results: Seventeen trials met the eligibility criteria, including 1,802 ACS patients undergoing PCI. The meta-analysis showed that STS significantly reduced high-sensitivity C-reactive protein (hs-CRP) levels (mean difference [MD = -2.35, 95% CI (-3.84, -0.86), p = 0.002], tumor necrosis factor-alpha (TNF-α) levels (standard mean difference [SMD = -3.29, 95%CI (-5.15, -1.42), p = 0,006], matrix metalloproteinase-9 (MMP-9) levels [MD = -16.24, 95%CI (-17.24, -15.24), p < 0.00001], and lipid peroxidation (LPO) levels [MD = -2.32, 95%CI (-2.70, -1.93), p < 0.00001], and increased superoxide dismutase (SOD) levels [SMD = 1.46, 95%CI (0.43, 2.49), p = 0,006] in patients with ACS. In addition, STS significantly decreased the incidence of major adverse cardiovascular events (relative risk = 0.54, 95%CI [0.44, 0.66], p < 0.00001). The quality of evidence for the outcomes was assessed to be very low to medium. Conclusion: STS can safely and effectively reduce the levels of hs-CRP, TNF-α, MMP-9, and LPO and increase the level of SOD in patients with ACS treated with PCI. It can also reduce the incidence of adverse cardiovascular events. However, these findings require careful consideration due to the small number of included studies, high risk of bias, and low to moderate evidence. In the future, more large-scale and high-quality RCTs will be needed as evidence in clinical practice.

DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation.

Plasma cell-free DNA (cfDNA) are small molecules generated through a non-random fragmentation procedure. Despite commendable translational values in cancer liquid biopsy, however, the biology of cfDNA, especially the principles of cfDNA fragmentation, remains largely elusive. Through orientation-aware analyses of cfDNA fragmentation patterns against the nucleosome structure and integration with multidimensional functional genomics data, here we report a DNA methylation - nuclease preference - cutting end - size distribution axis, demonstrating the role of DNA methylation as a functional molecular regulator of cfDNA fragmentation. Hence, low-level DNA methylation could increase nucleosome accessibility and alter the cutting activities of nucleases during DNA fragmentation, which further leads to variation in cutting sites and size distribution of cfDNA. We further develop a cfDNA ending preference-based metric for cancer diagnosis, whose performance has been validated by multiple pan-cancer datasets. Our work sheds light on the molecular basis of cfDNA fragmentation towards broader applications in cancer liquid biopsy.

The Preparation of Covalent Bonding COF-TpBD Coating in Arrayed Nanopores of Stainless Steel Fiber for Solid-Phase Microextraction of Polycyclic Aromatic Hydrocarbons in Water.

Covalent organic framework (COF)-TpBD was grafted on the arrayed nanopores of stainless steel fiber (SSF) with (3-aminopropyl) triethoxysilane as the cross-linking agent. The prepared SSF bonded with COF-TpBD showed high thermal and chemical stability and excellent repeatability. The prepared SSF bonded with COF-TpBD was also used for the solid-phase microextraction (SPME) of seven kinds of polycyclic aromatic hydrocarbons (PAHs) in actual water samples, followed by gas chromatography with flame ionization detection (GC-FID) determination, which exhibited low limits of detection (LODs), good relative standard deviation (RSD) and high recoveries.

Radiation-induced eosinophil increase ratio predicts patient outcomes in non-small celllung cancer.

Background and purpose: Radiotherapy (RT) is a double-edged sword in regulating immune responses. This study aimed to investigate the impact of thoracic RT on circulating eosinophils and its association with patient outcomes in non-small cell lung cancer (NSCLC). Materials and methods: This retrospective study included 240 patients with advanced NSCLC treated with definitive thoracic RT from January 2012 to January 2020. Statistics included Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS), multivariate Cox analyses to identify significant variables, and Spearman's correlation to qualify the relationship between dose-volume histogram (DVH) parameters and EIR. Results: Absolute eosinophil counts (AECs) showed an increasing trend during RT and an obvious peak in the 1st month after RT. Thresholds of eosinophil increase ratio (EIR) at the 1st month after RT for both OS and PFS were 1.43. Patients with high EIR above 1.43 experienced particularly favorable clinical outcomes (five-year OS: 21% versus 10%, P<0.0001; five-year PFS: 10% versus 8%, P=0.014), but may not derive PFS benefit from the addition of chemotherapy to RT. The higher a patient's EIR, the larger the potential benefit in the absence of chemotherapy. DVH parameters including heart mean dose and heart V10 were negatively associated with EIR. None of these DVH parameters was correlated with the clinical outcomes. Conclusion: EIR may serve as a potential biomarker to predict OS and PFS in NSCLC patients treated with RT. These findings require prospective studies to evaluate the role of such prognostic marker to identify patients at risk to tailor interventions.

Guanmaitong Granule Attenuates Atherosclerosis by Inhibiting Inflammatory Immune Response in ApoE-/- Mice Fed High-Fat Diet.

Background: Atherosclerosis (AS) is the leading cause of cardiovascular diseases, such as myocardial infarction and stroke. Guanmaitong granule (GMTG) is a TCM (Traditional Chinese medicine) prescribed to treat AS. However, its mechanism remains unclear. Methods: We obtained reliable ingredients and targets of GMTG using the HERB database. AS-related targets were obtained from HERB and GeneCards databases. The target database was constructed by intersecting the ingredients of GMTG with the AS-related targets. STRING and Cytoscape were used to create protein-protein interaction (PPI) network and screen core targets. GO enrichment analysis and KEGG pathway analyses were performed using R. Finally, the ApoE-/- mice AS model was induced by a high-fat diet (HFD) for in vivo validation of core pathways and targets. Results: A total of 124 ingredients and 418 potential targets of GMTG for treating AS were obtained. Numerous ingredients and targets were related to Panax notoginseng, Salvia miltiorrhiza, and Astragalus. Most core targets and pathways were involved in the inflammatory immune response. GMTG could decrease serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol, and oxidized low-density lipoprotein level and increase the serum high-density lipoprotein-cholesterol level. Furthermore, GMTG reduced the plaque burden and promoted plaque remodeling by reducing plaque area, lipid deposition, foam cell content, and collagen fiber content in the plaque in the aortic root of ApoE-/- mice. GMTG inhibited systemic and plaque inflammatory immune response and increased plaque stability by inhibiting the excessive release of the TLR4/MyD88/NF-κB pathway-induced inflammatory cytokines, tumor necrosis factor, interleukin-6, and interleukin-1 beta. Conclusion: Radix notoginseng, Radix salviae liguliobae, and Radix astragali are the main ingredients of GMTG for treating AS. Further, GMTG could regulate the level of serum lipids and inhibit inflammatory immune response, which resulted in anti-AS effects such as plaque stabilization, reduction of plaque burden, and plaque remodeling. GMTG is a promising multi-target treatment for AS.

Application of network pharmacology and molecular docking approach to explore active compounds and potential pharmacological mechanisms of Aconiti Lateralis Radix Praeparata and Lepidii Semen Descurainiae Semen for treatment of heart failure.

BACKGROUND: Heart failure (HF) is the end stage of the development of heart disease, whose prognosis is poor. The previous research of our team indicated that the formulae containing Aconiti Lateralis Radix Praeparata and Lepidii Semen Descurainiae Semen (ALRP-LSDS) could inhibit myocardial hypertrophy, inhibit cardiomyocyte apoptosis, delay myocardial remodeling (REM), and improve the prognosis of patients with HF effectively. In order to explore the mechanism of ALRP-LSDS for the treatment of HF, a combined approach of network pharmacology and molecular docking was conducted. METHODS: Public database TCMSP was used to screen the active compounds of ALRP-LSDS. The targets of screened active compounds were obtained from the TCMSP database and predicted using the online analysis tool PharmMapper. The targets of HF were obtained from 6 databases including GeneCards, OMIM, DrugBank, TTD, PharmGKB, and DisGeNET. Protein-protein interaction and enrichment analysis were performed, respectively, by STRING and Metascape online tools after merging the targets of active compounds and HF. Cytoscape software was used to conduct networks. Finally, molecular docking was performed by Vina to verify the correlation between key targets and active compounds. RESULTS: Final results indicated that the active compounds including ß-sitosterol, isorhamnetin, quercetin, kaempferol, and (R)-norcoclaurine, the targets including AKT1, CASP3, and MAPK1 might be the main active compounds and key targets of ALRP-LSDS for the treatment of HF separately. The binding ability of AKT1 to the main active compounds was better compared with the other 2 key targets, which means it might be more critical. The pathways including AGE-RAGE signaling pathway in diabetic complications, Pathways in cancer, and Fluid shear stress and atherosclerosis might play important roles in the treatment of HF with ALRP-LSDS. In general, ALRP-LSDS could inhibit cardiomyocyte apoptosis, delay REM, and improve cardiac function through multicompound, multitarget, and multipathway, which contributes to the treatment of HF. CONCLUSIONS: Based on the combined approach of network pharmacology and molecular docking, this study screened out the main active compounds, key targets, and main pathways of ALRP-LSDS for the treatment of HF, and revealed its potential mechanisms, providing a theoretical basis for further research.

Calycosin Alleviates Doxorubicin-Induced Cardiotoxicity and Pyroptosis by Inhibiting NLRP3 Inflammasome Activation.

Calycosin (CAL) is the main active component present in Astragalus and reportedly possesses diverse pharmacological properties. However, the cardioprotective effect and underlying mechanism of CAL against doxorubicin- (DOX-) induced cardiotoxicity need to be comprehensively examined. Herein, we aimed to investigate whether the cardioprotective effects of CAL are related to its antipyroptotic effect. A cardiatoxicity model was established by stimulating H9c2 cells and C57BL/6J mice using DOX. In vitro, CAL increased H9c2 cell viability and decreased DOX-induced pyroptosis via NLRP3, caspase-1, and gasdermin D signaling pathways in a dose-dependent manner. In vivo, CAL-DOX cotreatment effectively suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis via the same molecular mechanism. Next, we used nigericin (Nig) and NLRP3 forced overexpression to determine whether CAL imparts antipyroptotic effects by inhibiting the NLRP3 inflammasome in vitro. Furthermore, CAL suppressed DOX-induced mitochondrial oxidative stress injury in H9c2 cells by decreasing the generation of reactive oxygen species and increasing mitochondrial membrane potential and adenosine triphosphate. Likewise, CAL attenuated the DOX-induced increase in malondialdehyde content and decreased superoxide dismutase and glutathione peroxidase activities in H9c2 cells. In vivo, CAL afforded a protective effect against DOX-induced cardiac injury by improving myocardial function, inhibiting brain natriuretic peptide, and improving the changes of the histological morphology of DOX-treated mice. Collectively, our findings confirmed that CAL alleviates DOX-induced cardiotoxicity and pyroptosis by inhibiting NLRP3 inflammasome activation in vivo and in vitro.