Association of Ground Glass Opacities with Systemic Inflammation and Progression of Emphysema.

RATIONAL: Ground glass opacities (GGO) in the absence of interstitial lung disease are understudied. OBJECTIVE: To assess the association of GGO with white blood cells (WBCs) and progression of quantified chest CT emphysema. METHODS: We analyzed data of participants in the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). Chest radiologists and pulmonologists labeled regions of the lung as GGO and adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGO (%GGOAMFM). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGOAMFM with WBC, changes in %emphysema, and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Among 2,714 participants, 1,680 had COPD and 1,034 had normal spirometry. Among COPD participants, based on the multivariable analysis, current smoking and chronic productive cough was associated with higher %GGOAMFM. Higher %GGOAMFM was cross-sectionally associated with higher WBCs and neutrophils levels. Higher %GGOAMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at one-year follow visit by 11.7% (Relative increase; 95%CI 7.5-16.1%;P<0.001). We found no association between %GGOAMFM and one-year FEV1 decline but %GGOAMFM was associated with exacerbations and all-cause mortality during a median follow-up time of 1,544 days (Interquartile Interval=1,118-2,059). Among normal spirometry participants, we found similar results except that %GGOAMFM was associated with progression to COPD at one-year follow-up. CONCLUSIONS: Our findings suggest that GGOAMFM is associated with increased systemic inflammation and emphysema progression.

Investigation of the pan-cancer property of FNDC1 and its molecular mechanism to promote lung adenocarcinoma metastasis.

BACKGROUND: Fibronectin type III domain containing 1 (FNDC1) has been associated with the metastasis of many tumors, but its function in lung cancer remains uncertain. METHODS: FNDC1 expression was analyzed in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx), evaluate its prognostic value. Gene Set Enrichment Analysis (GSEA) enrichment analysis of differential expression of FNDC1 in lung cancer. The expression of FNDC1 was detected in five types of lung cancer cells, and screened to establish FNDC1 stable knockdown cell strains. To observe the migration and invasion ability of lung cancer cells after FNDC1 knockdown. Finally, we used rhIL-6 to interfere with the stable knockdown of FNDC1 in A549 cells and observed the recovery of migration and invasion. RESULT: Our results showed that FNDC1 expression was increased in 21 tumor tissues, including lung cancer, and was associated with poor prognosis in five cancers, including lung adenocarcinoma (LUAD) (P < 0.05). GSEA enrichment analysis showed that FNDC1 was related to the pathways involved the JAK-STAT signaling pathway. Stable knockdown of FNDC1 in A549 and H292 cells resulted in decreased migration and invasion ability of both cells, accompanied by decreased expression of MMP-2 and Snail, and a significant decline in the expression of p-JAK2 and p-STAT3. The suppressive effect of FNDC1 knockdown on lung cancer cell metastasis counteracted by the JAK-STAT agonist rhIL-6 were presented in the nude mouse metastatic tumor model. CONCLUSION: FNDC1 is implicated in poor prognosis of a diverse range of malignant tumors, which can promote metastasis and invasion of lung cancer through the JAK2-STAT3 signaling pathway.

Deciphering the molecular mechanism of Bu Yang Huan Wu Decoction in interference with diabetic pulmonary fibrosis via regulating oxidative stress and lipid metabolism disorder.

BACKGROUND: Diabetes mellitus type 2 and pulmonary fibrosis have been found to be closely related in clinical practice. Diabetic pulmonary fibrosis (DPF) is a complication of diabetes mellitus, but its treatment has yet to be thoroughly investigated. Bu Yang Huan Wu Decoction (BYHWD) is a well-known traditional Chinese prescription that has shown great efficacy in treating pulmonary fibrosis with hypoglycemic and hypolipidemic effects. METHODS: The active ingredients of BYHWD and the corresponding targets were retrieved from the Traditional Chinese Medicine Systematic Pharmacology Database (TCMSP) and SymMap2. Disease-related targets were obtained from the GeneCard, OMIM and CTD databases. GO enrichment and KEGG pathway enrichment were carried out using the DAVID database. AutoDock Vina software was employed to perform molecular docking. Molecular dynamics simulations of proteinligand complexes were conducted by Gromacs. Animal experiments were further performed to validate the effects of BYHWD on the selected core targets, markers of oxidative stress, serum lipids, blood glucose and pulmonary fibrosis. RESULTS: A total of 84 active ingredients and 830 target genes were screened in BYHWD, among which 56 target genes intersected with DPF-related targets. Network pharmacological analysis revealed that the active ingredients can regulate target genes such as IL-6, TNF-α, VEGFA and CASP3, mainly through AGE-RAGE signaling pathway, HIF-1 signaling pathway and TNF signaling pathway. Molecular docking and molecular dynamics simulations suggested that IL6-astragaloside IV, IL6-baicalein, TNFα-astragaloside IV, and TNFα-baicalein docking complexes could bind stably. Animal experiments showed that BYHWD could reduce the expression of core targets such as VEGFA, CASP3, IL-6 and TNF-α. In addition, BYHWD could reduce blood glucose, lipid, and MDA levels in DPF while increasing the activities of SOD, CAT and GSH-Px. BYHWD attenuated the expression of HYP and collagen I, mitigating pathological damage and collagen deposition within lung tissue. CONCLUSIONS: BYHWD modulates lipid metabolism disorders and oxidative stress by targeting the core targets of IL6, TNF-α, VEGFA and CASP3 through the AGE-RAGE signaling pathway, making it a potential therapy for DPF.

Integrated study reveals mechanism of Tripterygium Wilfordii against cholangiocarcinoma based on bioinformatics approaches and molecular dynamics simulation.

BACKGROUND: Tripterygium wilfordii Hook. f. (TW) shows anticancer activity, and no study has comprehensively investigated the effects of TW in treating cholangiocarcinoma (CHOL). This study was designed to identify the therapeutic role and the mechanism of TW against CHOL to obtain anti-CHOL candidate components and targets. METHODS: Ingredients of TW were collected from the Traditional Chinese Medicine System Pharmacology Database and literature. Limma package and weighted gene co-expression network analysis were used to identify the genes related to CHOL. Enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) was performed by R package Cluster-Profiler and Metascape, respectively. Protein-Protein Interaction (PPI) network was used to select core genes in the treatment of CHOL by TW, followed by GEPIA2, UALCAN database, and ROC curves to assess their diagnostic and prognostic capability. Molecular docking and molecular dynamics simulation were applied to explore the binding affinity and stability of the complex between the bioactive ingredients in TW and core targets. RESULTS: A total of 67 ingredients in TW were collected, and 495 genes were obtained as genes of CHOL. 55 common TW-CHOL targets were identified. 171 biological process terms and 100 KEGG pathways were enriched. 12 genes were regarded as core genes through PPI analysis, such as CYP3A4, CES1, GC, and PLG, whose good diagnostic and prognostic capability were identified. Ten ingredients were selected through the construction of Herb-Components-Targets-Disease network. Molecular docking and molecular dynamics simulation both confirmed the good binding affinity and stability of the ligand-protein complexes. CONCLUSION: This study identified the therapeutic role and predicted the mechanism of TW against CHOL, where TW may combat CHOL through the regulation of metabolic conditions of the body, bile acid secretion, xenobiotics metabolism, and the inflammatory response. Celastrol, triptonide, triptolide and wilforlide A emerged as promising anti-CHOL candidates. So, this study offered a reference for the treatment of CHOL and the development of anti-CHOL drugs.

Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

Association between antihypertensive drugs and oral cancer: a drug target Mendelian randomization study.

Background: Recent reports have suggested that antihypertensive drugs may play an oncogenic role in common cancers, but it is still uncertain whether this could influence the risk of oral cancer. Through two-sample Mendelian randomization (MR), we sought to assess the causal effect of antihypertensive drugs on oral cancer outcomes. Methods: To proxy the exposure of antihypertensive drugs, we utilized two genetic instruments, including expression quantitative trait loci of drug target genes and genetic variants within or around drug target genes related to blood pressure from genome-wide association studies. Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) were employed to compute the instrument effect estimates. Results: It was observed through IVW-MR analysis that there is a positive relationship between KCNH2 (target of beta-adrenoceptor blockers)-mediated blood pressure and oral cancer (odds ratio [OR] = 1.197, 95% confidence interval [CI] = 1.028-1.394). Similarly, SMR analysis demonstrated that a higher expression of KCNH2 (target of beta-adrenoceptor blockers) was linked to a greater risk of oral cancer (OR = 2.223, 95% CI = 1.094-4.516). Both analyses yielded no consistent evidence of other associations. Conclusion: This two-sample MR study proposed a latent causal association between KCNH2 (target of beta-adrenoceptor blockers) inhibition and diminished risk of oral cancer.

Exploring the role and mechanism of Astragalus membranaceus and radix paeoniae rubra in idiopathic pulmonary fibrosis through network pharmacology and experimental validation.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic disease with an unclear etiology and no effective treatment. This study aims to elucidate the pathogenic mechanism networks involving multiple targets and pathways in IPF. Extracts and metabolites of Astragalus membranaceus (AM) and Radix paeoniae rubra (RPR), two well-known traditional Chinese medicines, have demonstrated therapeutic effects on IPF. However, the underlying mechanisms of AM and RPR remain unclear. Utilizing network pharmacology analysis, differentially expressed genes (DEGs) associated with IPF were obtained from the GEO database. Targets of AM and RPR were identified using the TCM Systems Pharmacology Database and Analysis Platform and SwissTargetPrediction. A protein-protein interaction (PPI) network was subsequently constructed and analyzed using the STRING database and Cytoscape software. Gene ontology enrichment analysis and kyoto encyclopedia of genes and genomes analysis were conducted using Metascape. Additionally, a component-target-pathway network and a Sankey diagram were employed to identify the main active components, and molecular docking was performed between these components and proteins encoded by key targets. Finally, in vivo studies were conducted based on network pharmacology. A total of 117 common targets between DEGs of IPF and drug targets were identified and included in the PPI network, in which AKT1, MAPK3, HSP90AA1, VEGFA, CASP3, JUN, HIF1A, CCND1, PTGS2, and MDM2 were predicted as key targets. These 117 targets were enriched in the PI3K-AKT pathway, HIF-1 signaling pathway, apoptosis, and microRNAs in cancer. Astragaloside III, (R)-Isomucronulatol, Astragaloside I, Paeoniflorin, and ß-sitosterol were selected as the main active components. Docking scores ranged from - 4.7 to - 10.7 kcal/mol, indicating a strong binding affinity between the main active compounds and key targets. In vivo studies have indeed shown that AM and RPR can alleviate the pathological lung fibrotic damage caused by bleomycin treatment. The treatment with AM and RPR resulted in a reduction of mRNA levels for key targets AKT1, HSP90AA1, CASP3, MAPK3, and VEGFA. Additionally, the protein expression levels of AKT1, HSP90AA1, and VEGFA were also reduced. These results support the therapeutic potential of AM and RPR in ameliorating pulmonary fibrosis and provide insight into the molecular mechanisms involved in their therapeutic effects.

Integrative single-cell RNA and ATAC sequencing reveals that the FOXO1-PRDX2-TNF axis regulates tendinopathy.

Introduction: Tendinopathy, the most common form of chronic tendon disorder, leads to persistent tendon pain and loss of function. Profiling the heterogeneous cellular composition in the tendon microenvironment helps to elucidate rational molecular mechanisms of tendinopathy. Methods and results: In this study, through a multi-modal analysis, a single-cell RNA- and ATAC-seq integrated tendinopathy landscape was generated for the first time. We found that a specific cell subpopulation with low PRDX2 expression exhibited a higher level of inflammation, lower proliferation and migration ability, which not only promoted tendon injury but also led to microenvironment deterioration. Mechanistically, a motif enrichment analysis of chromatin accessibility showed that FOXO1 was an upstream regulator of PRDX2 transcription, and we confirmed that functional blockade of FOXO1 activity induced PRDX2 silencing. The TNF signaling pathway was significantly activated in the PRDX2-low group, and TNF inhibition effectively restored diseased cell degradation. Discussion: We revealed an essential role of diseased cells in tendinopathy and proposed the FOXO1-PRDX2-TNF axis is a potential regulatory mechanism for the treatment of tendinopathy.

Mechanism exploration and prognosis study of Astragali Radix-Spreading hedyotis herb for the treatment of lung adenocarcinoma based on bioinformatics approaches and molecular dynamics simulation.

Background: Herb pair of Astragali Radix (AR) and Spreading Hedyotis Herb (SH) has been frequently prescribed in clinical for the treatment of lung cancer owing to its favorable efficacy. Yet, the mechanism under the therapeutic effects remained unveiled, which has limited its clinical applications, and new drug development for lung cancer. Methods: The bioactive ingredients of AR and SH were retrieved from the Traditional Chinese Medicine System Pharmacology Database, with the targets of obtained components predicted by Swiss Target Prediction. Genes related to lung adenocarcinoma (LUAD) were acquired from GeneCards, OMIM and CTD databases, with the hub genes of LUAD screened by CTD database. The intersected targets of LUAD and AR-SH were obtained by Venn, with David Database employed to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Survival analysis of the hub genes of LUAD was carried out using TCGA-LUAD dataset. Molecular docking of core proteins and active ingredients was performed by Auto-Dock Vina software, followed by molecular dynamics simulations of protein-ligand complexes with well-docked conformations. Results: 29 active ingredients were screened out with 422 corresponding targets predicted. It is revealed that AR-SH can act on various targets such as EGFR, MAPK1, and KARS by ursolic acid (UA), Astragaloside IV(ASIV), and Isomucronulatol 7,2'-di-O-glucoside (IDOG) to alleviate the symptoms of LUAD. Biological processes involved are protein phosphorylation, negative regulation of apoptotic process, and pathways involved are endocrine resistance, EGFR tyrosine kinase inhibitor resistance, PI3K-Akt, and HIF-1 pathway. Molecular docking analysis indicated that the binding energy of most of the screened active ingredients to proteins encoded by core genes was less than -5.6 kcal/mol, with some active ingredients showing even lower binding energy to EGFR than Gefitinib. Three ligand-receptor complexes including EGFR-UA, MAPK1-ASIV, and KRAS-IDOG were found to bind relatively stable by molecular dynamics simulation, which was consistent with the results of molecule docking. Conclusion: We suggested that the herb pair of AR-SH can act on targets like EGFR, MAPK1 and KRAS by UA, ASIV and IDOG, to play a vital role in the treatment and the enhancement of prognosis of LUAD.

Predicting severe chronic obstructive pulmonary disease exacerbations using quantitative CT: a retrospective model development and external validation study.

BACKGROUND: Quantitative CT is becoming increasingly common for the characterisation of lung disease; however, its added potential as a clinical tool for predicting severe exacerbations remains understudied. We aimed to develop and validate quantitative CT-based models for predicting severe chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: We analysed the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS) cohort, a multicentre study done at 12 clinical sites across the USA, of individuals aged 40-80 years from four strata: individuals who never smoked, individuals who smoked but had normal spirometry, individuals who smoked and had mild to moderate COPD, and individuals who smoked and had severe COPD. We used 3-year follow-up data to develop logistic regression classifiers for predicting severe exacerbations. Predictors included age, sex, race, BMI, pulmonary function, exacerbation history, smoking status, respiratory quality of life, and CT-based measures of density gradient texture and airway structure. We externally validated our models in a subset from the Genetic Epidemiology of COPD (COPDGene) cohort. Discriminative model performance was assessed using the area under the receiver operating characteristic curve (AUC), which was also compared with other predictors, including exacerbation history and the BMI, airflow obstruction, dyspnoea, and exercise capacity (BODE) index. We evaluated model calibration using calibration plots and Brier scores. FINDINGS: Participants in SPIROMICS were enrolled between Nov 12, 2010, and July 31, 2015. Participants in COPDGene were enrolled between Jan 10, 2008, and April 15, 2011. We included 1956 participants from the SPIROMICS cohort who had complete 3-year follow-up data: the mean age of the cohort was 63·1 years (SD 9·2) and 1017 (52%) were men and 939 (48%) were women. Among the 1956 participants, 434 (22%) had a history of at least one severe exacerbation. For the CT-based models, the AUC was 0·854 (95% CI 0·852-0·855) for at least one severe exacerbation within 3 years and 0·931 (0·930-0·933) for consistent exacerbations (defined as ≥1 acute episode in each of the 3 years). Models were well calibrated with low Brier scores (0·121 for at least one severe exacerbation; 0·039 for consistent exacerbations). For the prediction of at least one severe event during 3-year follow-up, AUCs were significantly higher with CT biomarkers (0·854 [0·852-0·855]) than exacerbation history (0·823 [0·822-0·825]) and BODE index 0·812 [0·811-0·814]). 6965 participants were included in the external validation cohort, with a mean age of 60·5 years (SD 8·9). In this cohort, AUC for at least one severe exacerbation was 0·768 (0·767-0·769; Brier score 0·088). INTERPRETATION: CT-based prediction models can be used for identification of patients with COPD who are at high risk of severe exacerbations. The newly identified CT biomarkers could potentially enable investigation into underlying disease mechanisms responsible for exacerbations. FUNDING: National Institutes of Health and the National Heart, Lung, and Blood Institute.

Reliability assessment of transformer insulating oil using accelerated life testing.

To improve the reliability and reduce the maintenance cost of transformer oil, a life prediction of transformer oil is needed so that the maintenance of transformer can be performed correctly. However, it is difficult to predict the reliable lifetime of transformer oil accurately because of its unkind operating condition at different environments. To solve this problem, based on the theory of accelerated life testing (ALT), a reliability assessment method for transformer insulating oil on a normal operational conditions is proposed. An inverse power Weibull distribution model for insulating oil lifetime with voltage is built. Numerical procedure of model parameter estimation is presented, the variances of model parameters and reliability indices, which including mean lifetime, reliability, reliable lifetime at given reliability and failure rate, are derived. The feasibility and correctness of the proposed method are validated by real lifetime data of transformer insulating oil in literature. The reliability of transformer insulating oil used at normal usage conditions are predicted by the proposed method, and the point and interval estimations of reliability indices are evaluated. The results show that reliable lifetime and mean lifetime under reliability limit should be considered simultaneously in repair or replacement of transformer insulating oil.

Ocruranus-Eohalobia Sclerites from the Cambrian Stage 2 Yanjiahe Formation in South China: Scleritome Reconstruction and Zoological Affinity.

The isolated sclerites of the Ocruranus and Eohalobia group are abundant among the early Cambrian small shelly fossil assemblages, which were recently assigned to the same scleritome as an early member of the polyplacophoran (chiton) stem lineage. However, the scleritome reconstruction and zoological affinities of these sclerites are still controversial due to the lack of exceptionally preserved articulated specimens with in-situ sclerites. Herein, we report new specimens of Ocruranus and Eohalobia sclerites from Member 5 of the Yanjiahe Formation, which provide new insights into the reconstruction of the original scleritome. The Eohalobia sclerites from the Yanjiahe Formation have an extended and upfolded proximal field with dense wrinkles, which seems to be a weakly mineralized structure and acted as a joint with another sclerite, Ocruranus. Comparing the butterfly-shaped proximal field on a unique sclerite of Eohalobia with the sub-apical field on Ocruranus sclerites suggests that the original scleritome of this group may consist of only two types of sclerites: the Ocruranus-type and the Eohalobia-type. The polygonal structure on the internal mold of Eohalobia sclerites is interpreted herein as the muscle attachment zone; their distribution corresponds well with that of the modern chitons, which provides strong evidence to support the close relationship between the Ocruranus-Eohalobia group and the Polyplacophora.

Pulmonary Blood Volume Among Older Adults in the Community: The MESA Lung Study.

BACKGROUND: The pulmonary vasculature is essential for gas exchange and impacts both pulmonary and cardiac function. However, it is difficult to assess and its characteristics in the general population are unknown. We measured pulmonary blood volume (PBV) noninvasively using contrast enhanced, dual-energy computed tomography to evaluate its relationship to age and symptoms among older adults in the community. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) is an ongoing community-based, multicenter cohort. All participants attending the most recent MESA exam were selected for contrast enhanced dual-energy computed tomography except those with estimated glomerular filtration rate <60 mL/min per 1.73 m2. PBV was calculated by material decomposition of dual-energy computed tomography images. Multivariable models included age, sex, race/ethnicity, education, height, weight, smoking status, pack-years, and scanner model. RESULTS: The mean age of the 727 participants was 71 (range 59-94) years, and 55% were male. The race/ethnicity distribution was 41% White, 29% Black, 17% Hispanic, and 13% Asian. The mean±SD PBV in the youngest age quintile was 547±180 versus 433±194 mL in the oldest quintile (P<0.001), with an approximately linear decrement of 50 mL per 10 years of age ([95% CI, 32-67]; P<0.001). Findings were similar with multivariable adjustment. Lower PBV was associated independently with a greater dyspnea after a 6-minute walk (P=0.04) and greater composite dyspnea symptom scores (P=0.02). Greater PBV was also associated with greater height, weight, lung volume, Hispanic race/ethnicity, and nonsmoking history. CONCLUSIONS: Pulmonary blood volume was substantially lower with advanced age and was associated independently with greater symptoms scores in the elderly.

Platinum-Catalysed Selective Aerobic Oxidation of Methane to Formaldehyde in the Presence of Liquid Water.

The aerobic, selective oxidation of methane to C1 -oxygenates remains a challenge, due to the more facile, consecutive oxidation of formed products to CO2 . Here, we report on the aerobic selective oxidation of methane under continuous flow conditions, over platinum-based catalysts yielding formaldehyde with a high selectivity (reaching 90 % for Pt/TiO2 and 65 % over Pt/Al2 O3 ) upon co-feeding water. The presence of liquid water under reaction conditions increases the activity strongly attaining a methane conversion of 1-3 % over Pt/TiO2 . Density-functional theory (DFT) calculations show that the preferential formation of formaldehyde is linked to the stability of the di-σ-hydroxy-methoxy species on platinum, the preferred carbon-containing species on Pt(111) at a high chemical potential of water. Our findings provide novel insights into the reaction pathway for the Pt-catalysed, aerobic selective oxidation of CH4 .

The Network Pharmacology Study of Dahuang Fuzi Decoction for Treating Incomplete Intestinal Obstruction.

Objective: To explore the mechanism of Dahuang Fuzi decoction in the treatment of incomplete intestinal obstruction (IIO) based on network pharmacology and molecular docking. Methods: The chemical components of Rhubarb, Aconite, and Asarum were searched by the Traditional Chinese Medicine Systems Pharmacology database, where the possible active components were screened by oral bioavailability and drug likeness as filtering indicators. The relevant targets in the Swiss Target Prediction database were obtained according to the structure of the chemical components confirmed by the PubChem database. Disease targets of IIO were collected using GeneCards and OMIM databases. We obtained the cross-target using VENNY to capture the common targets. PPI analysis was performed on the intersection genes combined with Cytoscape 3.7.2. Gene Ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were carried out by David database. The core targets and active ingredients were molecularly docked through AutoDock Vina software to predict the detailed molecular mechanism of Dahuang Fuzi decoction for treating IIO. Results: There are 45 active components in Dahuang Fuzi decoction, with 709 corresponding targets, 538 IIO targets, and 97 common targets, among which kaempferol, deltoin, and eupatin are the main active ingredients. 10 core targets were obtained by protein-protein interaction network analysis. Through GO enrichment analysis, it was found that Dahuang Fuzi decoction may be involved in biological processes such as signal transduction, anti-apoptosis, promotion of gene expression, regulation of cell proliferation, and differentiation. Besides, KEGG pathway analysis revealed that it mainly relates to PI3K-AKT signal pathway and HIF-1 signal pathway, etc. Molecular docking results showed that the active ingredients of Dahuang Fuzi decoction possess a good binding activity with the core targets. Conclusion: Dahuang Fuzi decoction may act on target genes such as TNF, IL6, AKT1, VEGFA, SRC, EGFR, and STAT3 through active ingredients such as kaempferol, deltoin, and eupatin to regulate signaling pathways such as PI3K-AKT and HIF-1 and reduce the expression of various inflammatory factors such as TNF-α, IL-6, iNOS, and COX-2 to play a role in the treatment of IIO.

Single-Cell Profiling of Tumor Microenvironment Heterogeneity in Osteosarcoma Identifies a Highly Invasive Subcluster for Predicting Prognosis.

Osteosarcoma is the most common malignant bone tumor in adolescents, and metastasis is the key reason for treatment failure and poor prognosis. Once metastasis occurs, the 5-year survival rate is only approximately 20%, and assessing and predicting the risk of osteosarcoma metastasis are still difficult tasks. In this study, cellular communication between tumor cells and nontumor cells was identified through comprehensive analysis of osteosarcoma single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, illustrating the complex regulatory network in the osteosarcoma microenvironment. In line with the heterogeneity of osteosarcoma, we found subpopulations of osteosarcoma cells that highly expressed COL6A1, COL6A3 and MIF and were closely associated with lung metastasis. Then, BCDEG, a reliable risk regression model that could accurately assess the metastasis risk and prognosis of patients, was established, providing a new strategy for the diagnosis and treatment of osteosarcoma.

M2 Macrophage Derived Extracellular Vesicle-Mediated Transfer of MiR-186-5p Promotes Colon Cancer Progression by Targeting DLC1.

Colon cancer (CC) is one of the most common malignances in digestive tract. M2-polarized macrophages within the tumor microenvironment could facilitate CC cell growth by transferring molecules via extracellular vesicles, but the mechanisms are not fully elucidated. The current study aims to identify the possible effectors in M2 macrophage-derived extracellular vesicles (M2-EVs) and reveal related molecular mechanisms. In our study, we validated the promotion effects of M2-EVs on the proliferation and motility of CC cells, which was found to be dependent on the EVs enclosed molecules by a mild EVs digestion assay. Then we found that miR-186-5p was enriched in M2-EVs and was responsible for the tumor promoting functions of M2-EVs. Furthermore, mechanism investigation revealed M2-EVs transferring miR-186-5p inhibited DLC1 expression by targeting its 3'UTR, and restored DLC1 successfully neutralized the tumor-promoting effects of M2-EVs transferring miR-186-5p via inhibiting the ß-catenin pathway. Our study revealed that M2-EVs facilitates the growth and motility of CC cells by delivering the enclosed miR-186-5p, which directly targets DLC1 mRNAs and facilitates their degradation, which could provide a potential biomarker and therapeutic target for CC.

Single-cell profiling reveals that SAA1+ epithelial cells promote distant metastasis of esophageal squamous cell carcinoma.

Introduction: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers globally, with significant cell heterogeneity and poor prognosis. Distant metastasis in ESCC is one of the key factors that affects the prognosis of patients. Methods and results: Starting with the analysis of ESCC single-cell sequencing data, we constructed a single-cell atlas of ESCC in detail and clarified the cell heterogeneity within tumor tissues. Through analysis of epithelial-mesenchymal transition (EMT) levels, gene expression, and pathway activation, we revealed the existence of a novel subpopulation of SAA1+ malignant cells in ESCC that are highly aggressive and closely associated with distant metastasis of ESCC. In vitro wound healing and transwell assays confirmed a strong invasion capacity of ESCC tumor cells with high expression of SAA1. Then, we constructed an effective and reliable prediction model based on the gene expression pattern of SAA1+ malignant cell subpopulations and confirmed that patients in the high-risk group had significantly worse prognosis than those in the low-risk group in the training cohort, internal verification cohort and external verification cohort. Discussion: This manuscript contributes to exploration of the heterogeneity of ESCC tumor tissues and the search for new ESCC subpopulations with special biological functions. These results contribute to our understanding of the underlying mechanisms of distant metastasis of ESCC and thus provide a theoretical basis for improved therapies.

Menstrual cycle impacts lung structure measures derived from quantitative computed tomography.

OBJECTIVE: Quantitative computed tomography (qCT) is being increasingly incorporated in research studies and clinical trials aimed at understanding lung disease risk, progression, exacerbations, and intervention response. Menstrual cycle-based changes in lung function are recognized; however, the impact on qCT measures is currently unknown. We hypothesize that the menstrual cycle impacts qCT-derived measures of lung structure in healthy women and that the degree of measurement change may be mitigated in subjects on cyclic hormonal birth control. METHODS: Thirty-one non-smoking, healthy women with regular menstrual cycles (16 of which were on cyclic hormonal birth control) underwent pulmonary function testing and qCT imaging at both menses and early luteal phase time points. Data were evaluated to identify lung measurements which changed significantly across the two key time points and to compare degree of change across metrics for the sub-cohort with versus without birth control. RESULTS: The segmental airway measurements were larger and mean lung density was higher at menses compared to the early luteal phase. The sub-cohort with cyclic hormonal birth control did not have less evidence of measurement difference over the menstrual cycle compared to the sub-cohort without hormonal birth control. CONCLUSIONS: This study provides evidence that qCT-derived measures from the lung are impacted by the female menstrual cycle. This indicates studies seeking to use qCT as a more sensitive measure of cross-sectional differences or longitudinal changes in these derived lung measurements should consider acquiring data at a consistent time in the menstrual cycle for pre-menopausal women and warrants further exploration. KEY POINTS: • Lung measurements from chest computed tomography are used in multicenter studies exploring lung disease progression and treatment response. • The menstrual cycle impacts lung structure measurements. • Cyclic variability should be considered when evaluating longitudinal change with CT in menstruating women.

Comprehensive Analysis of the Effects of Genetic Ancestry and Genetic Characteristics on the Clinical Evolution of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC), a kind of malignant cancer, is associated with increasing morbidity and mortality. Patients with different genetic ancestries may respond differently to clinical treatment. The limited understanding of the influence of genetic ancestry and genetic characteristics on OSCC impedes the development of precision medicine. To provide a reference for clinical treatment, this study comprehensively analyzed multigenomic differences in OSCC patients with different genetic ancestries and their impact on prognosis. An analysis of data from OSCC patients with different genetic ancestries in The Cancer Genome Atlas (TCGA) showed that the overall survival (OS) of African (AFR) patients was lower than that of primarily European (EUR) patients, and differences were also observed in the tumor-stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs), which are associated with prognosis. FAT1 is a key mutant gene in OSCC, and it has inconsistent effects on clinical evolution for patients with diverse genetic characteristics. PIKfyve and CAPN9 showed a significant difference in mutation frequency between EUR and AFR; PIKfyve was related to Ki-67 expression, suggesting that it could promote tumor proliferation, and CAPN9 was related to the expression of Bcl-2, promoting tumor cell apoptosis. A variant methylation locus, cg20469139, was correlated with the levels of PD-L1 and Caspase-7 and modulated tumor cell apoptosis. A novel ceRNA model was constructed based on genetic ancestries, and it could accurately evaluate patient prognosis. More importantly, although T cell dysfunction scores could determine the potential of tumor immune escape, the efficacy was obviously affected by patients' genetic ancestries. To provide patients with more precise, personalized therapy and to further improve their quality of life and 5-year survival rate, the influence of genetic ancestry should be fully considered when selecting treatments.