Meta-analysis of the association between sex hormones and pulmonary fibrosis.

BACKGROUND: This study aimed to investigate the association between sex hormones and the risk of pulmonary fibrosis by conducting a meta-analysis of previously published studies. METHODS: We executed a comprehensive search of the PubMed, Embase, Cochrane Library, and Web of Science databases to locate pertinent studies published up to April 2024. We included studies that reported the association between sex hormones and the risk of pulmonary fibrosis. Standardized mean difference (SMD) with 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: A total of 10 articles, encompassing 1371 patients, were finally incorporated in this meta-analysis. Based on the evaluation of the included studies, it was observed that the levels of dehydroepiandrosterone sulfate (DHEA-S) (pooled SMD: -0.72, 95% CI: -1.21 to -0.24, p < 0.001), testosterone (pooled SMD: -1.25, CI: -2.39 and -0.11, p < 0.001) and estrogen (pooled SMD: -0.56, 95% CI: -0.96 to -0.15, p < 0.001) were significantly lower in patients with pulmonary fibrosis, whereas the levels of luteinizing hormone (LH) remained unaffected. Publication bias was ruled out through funnel plots. CONCLUSION: This meta-analysis indicates that reduced levels of DHEA-S, testosterone, estrogen may serve as potential risk factors for pulmonary fibrosis. There is a pressing need for additional studies to confirm this association and explore the underlying biological mechanisms. Clinicians should recognize the potential influence of sex hormones in the etiology of pulmonary fibrosis and consider this aspect during the patient management process.

Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial-mesenchymal trophic unit activation in asthma.

BACKGROUND AND PURPOSE: Airway epithelial cells (AECs) regulate the activation of epithelial-mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signalling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodelling is still obscure. EXPERIMENTAL APPROACH: The differing expressed genes in airway epithelia related to airway remodelling were screened and verified by RNA-sequencing and signalling pathway analysis. Then, the effects of increased cathepsin K (CTSK) in airway epithelia on airway remodelling and EMTU activation were identified both in vitro and in vivo, and the molecular mechanism was elucidated in the EMTU model. The potential of CTSK as an an effective biomarker of airway remodelling was analysed in an asthma cohort of differing severity. Finally, an inhibitor of CTSK was administered for potential therapeutic intervention for airway remodelling in asthma. KEY RESULTS: The expression of CTSK in airway epithelia increased significantly along with the development of airway remodelling in a house dust mite (HDM)-stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTUs by activation of the PAR2-mediated pathway. Blockade of CTSK inhibited EMTU activation and alleviated airway remodelling as an effective intervention target of airway remodelling. CONCLUSION AND IMPLICATIONS: Increased expression of CTSK in airway epithelia is involved in the development of airway remodelling in asthma through EMTU activation, mediated partly through the PAR2-mediated signalling pathway. CTSK is a potential biomarker for airway remodelling, and may also be a useful intervention target for airway remodelling in asthma patients.

Airway epithelial-derived exosomes induce acute asthma exacerbation after respiratory syncytial virus infection.

Acute asthma exacerbation refers to the progressive deterioration of asthma symptoms that is always triggered by virus infection represented by respiratory syncytial virus (RSV). After RSV infection, exaggerated Th2-mediated pulmonary inflammation is the critical pathological response of asthmatic patients with acute exacerbation. Significantly, airway epithelial cells, being the primary targets of RSV infection, play a crucial role in controlling the pulmonary inflammatory response by releasing airway epithelial cell-derived exosomes (AEC-Exos), which potentially influence the development of asthma. However, the specific role of AEC-Exos in acute asthma exacerbation after RSV infection remains obscure. The purpose of this study was to determine the distinct function of AEC-Exos in exacerbating acute asthma following RSV infection. Blockade of exosomes by GW reduce the enhanced pulmonary inflammation significantly. Specifically, the enhanced Th2 inflammation was induced by AEC-Exos thorough transportation of hsa-miR-155-5p-Sirtuin 1 (SIRT1) pathway during acute asthma exacerbation. Targeted inhibition of hsa-miR-155-5p blocks the exaggerated Th2 inflammation effectively in mice with acute asthma exacerbation. In summary, our study showed that during acute asthma exacerbation after RSV infection, AEC-Exos promote the enhanced Th2 inflammation through transportation of increased hsa-miR-155-5p, which was mediated partly through SIRT1-mediated pathway. hsa-miR-155-5p is a potential biomarker for early prediction of acute asthma exacerbation.

Systemic Inflammatory Response Index (SIRI) is associated with all-cause mortality and cardiovascular mortality in population with chronic kidney disease: evidence from NHANES (2001-2018).

Objective: To examine the correlation between SIRI and the probability of cardiovascular mortality as well as all-cause mortality in individuals with chronic kidney disease. Methods: A cohort of 3,262 participants from the US National Health and Nutrition Examination Survey (NHANES) database were included in the study. We categorized participants into five groups based on the stage of chronic kidney disease. A weighted Cox regression model was applied to assess the relationship between SIRI and mortality. Subgroup analyses, Kaplan-Meier survival curves, and ROC curves were conducted. Additionally, restricted cubic spline analysis was employed to elucidate the detailed association between SIRI and hazard ratio (HR). Results: This study included a cohort of 3,262 individuals, of whom 1,535 were male (weighted proportion: 42%), and 2,216 were aged 60 or above (weighted proportion: 59%). Following adjustments for covariates like age, sex, race, and education, elevated SIRI remained a significant independent risk factor for cardiovascular mortality (HR=2.50, 95%CI: 1.62-3.84, p<0.001) and all-cause mortality (HR=3.02, 95%CI: 2.03-4.51, p<0.001) in CKD patients. The restricted cubic spline analysis indicated a nonlinear relationship between SIRI and cardiovascular mortality, with SIRI>1.2 identified as an independent risk factor for cardiovascular mortality in CKD patients. Conclusion: Heightened SIRI independently poses a risk for both all-cause and cardiovascular mortality in chronic kidney disease patients, with potentially heightened significance in the early stages (Stage I to Stage III) of chronic kidney disease.

A comprehensive analysis of the role of QPRT in breast cancer.

To explore the clinical role of QPRT in breast cancer. The gene expression, methylation levels and prognostic value of QPRT in breast cancer was analyzed using TCGA data. Validation was performed using the data from GEO dataset and TNMPLOT database. Meta analysis method was used to pool the survival data for QPRT. The predictive values of QPRT for different drugs were retrieved from the ROC plot. The expression differences of QPRT in acquired drug-resistant and sensitive cell lines were analyzed using GEO datasets. GO and KEGG enrichment analysis were conducted for those genes which were highly co-expressed with QPRT in tissue based on TCGA data and which changed after QPRT knockdown. Timer2.0 was utilized to explore the correlation between QPRT and immune cells infiltration, and the Human Protein Atlas was used to analyse QPRT's single-cell sequencing data across different human tissues. The expression of QPRT in different types of macrophages, and the expression of QPRT were analysed after coculturing HER2+ breast cancer cells with macrophages. Additionally, TargetScan, Comparative Toxicogenomics and the connectivity map were used to research miRNAs and drugs that could regulate QPRT expression. Cytoscape was used to map the interaction networks between QPRT and other proteins. QPRT was highly expressed in breast cancer tissue and highly expressed in HER2+ breast cancer patients (P < 0.01). High QPRT expression levels were associated with worse OS, DMFS, and RFS (P < 0.01). Two sites (cg02640602 and cg06453916) were found to be potential regulators of breast cancer (P < 0.01). QPRT might predict survival benefits in breast cancer patients who received taxane or anthracycline. QPRT was associated with tumour immunity, especially in macrophages. QPRT may influence the occurrence and progression of breast cancer through the PI3K-AKT signalling pathway, Wnt signalling pathway, and cell cycle-related molecules.

Analysis of necroptosis-related prognostic genes and immune infiltration in idiopathic pulmonary fibrosis.

Background: IPF is an undetermined, progressive lung disease. Necroptosis is a type of programmed apoptosis, which involved in the pathogenesis of lung diseases like COPD and ARDS. However, necroptosis in IPF have not been adequately studied. This study aimed to investigate the necroptosis in IPF and the relationship between necroptosis and immune infiltration, to construct a prognostic prediction model of IPF based on necroptosis-related genes. Methods: GSE110147 was downloaded from the GEO database and utilized to analyze the expression of necroptosis-related differentially expressed genes (NRDEGs). Then NRDEGs were used to construct protein-protein interaction (PPI) networks in the STRING database, and Cytoscape software was used to identify and visualize hub genes. Necroptosis-related prognosticgenes were explored in GSE70866, and a prognostic prediction model was constructed. The ImmuCellAI algorithm was utilized to analyze the landscape of immune infiltration in GSE110147. The single-cell RNA sequencing dataset GSE122960 was used to explore the association between necroptosis and type II alveolar epithelial cells (AT II) in IPF. The GSE213001 and GSE93606 were used for external validation. The expression of prognostic genes was quantified using RT-qPCRin the IPF A549 cell model, and was further verified by western blotting in the bleomycin-induced pulmonary fibrosis mouse model. Results: It was observed that necroptosis-related signaling pathways were abundantly enriched in IPF. 29 NRDEGs were screened, of which 12 showed consistent expression trends in GSE213001. Spearman correlation analysis showed that the expression of NRDEGs was positively correlated with the infiltration of proinflammatory immune cells, and negatively correlated with the infiltration of anti-inflammatory immune cells. NRDEGs, including MLKL, were highly expressed in AT II of fibrotic lung tissue. A necroptosis-related prediction model was constructed based on 4 NRDEGsby the cox stepwise regression. In the validation dataset GSE93606, the prognostic prediction model showed good applicability. The verification results of RT-qPCR and western blotting showed the reliability of most of the conclusions. Conclusions: This study revealed that necroptosis existed in IPF and might occur in AT II. Necroptosis was associated with immune infiltration, suggesting that necroptosis of AT II might involve in IPF by activating immune infiltration and immune response.

Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model.

BACKGROUND: Airway epithelial cells (AECs) with impaired barrier function contribute to airway remodeling through the activation of epithelial-mesenchymal trophic units (EMTUs). Although the decreased expression of ITGB4 in AECs is implicated in the pathogenesis of asthma, how ITGB4 deficiency impacts airway remodeling remains obscure. OBJECTIVE: This study aims to determine the effect of epithelial ITGB4 deficiency on the barrier function of AECs, asthma susceptibility, airway remodeling, and EMTU activation. METHODS: AEC-specific ITGB4 conditional knockout mice (ITGB4-/-) were generated and an asthma model was employed by the sensitization and challenge of house dust mite (HDM). EMTU activation-related growth factors were examined in ITGB4-silenced primary human bronchial epithelial cells of healthy subjects after HDM stimulation. Dexamethasone, the inhibitors of JNK phosphorylation or FGF2 were administered for the identification of the molecular mechanisms of airway remodeling in HDM-exposed ITGB4-/- mice. RESULTS: ITGB4 deficiency in AECs enhanced asthma susceptibility and airway remodeling by disrupting airway epithelial barrier function. Aggravated airway remodeling in HDM-exposed ITGB4-/- mice was induced through the enhanced activation of EMTU mediated by Src homology domain 2-containing protein tyrosine phosphatase 2/c-Jun N-terminal kinase/Jun N-terminal kinase-dependent transcription factor/FGF2 (SHP2/JNK/c-Jun/FGF2) signaling pathway, which was partially independent of airway inflammation. Both JNK and FGF2 inhibitors significantly inhibited the aggravated airway remodeling and EMTU activation in HDM-exposed ITGB4-/- mice. CONCLUSIONS: Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model of asthma through enhanced EMTU activation that is regulated by the SHP2/JNK/c-Jun/FGF2 pathway.

A Comprehensive Mass Spectrometry-Based Workflow for Clinical Metabolomics Cohort Studies.

As a comprehensive analysis of all metabolites in a biological system, metabolomics is being widely applied in various clinical/health areas for disease prediction, diagnosis, and prognosis. However, challenges remain in dealing with the metabolomic complexity, massive data, metabolite identification, intra- and inter-individual variation, and reproducibility, which largely limit its widespread implementation. This study provided a comprehensive workflow for clinical metabolomics, including sample collection and preparation, mass spectrometry (MS) data acquisition, and data processing and analysis. Sample collection from multiple clinical sites was strictly carried out with standardized operation procedures (SOP). During data acquisition, three types of quality control (QC) samples were set for respective MS platforms (GC-MS, LC-MS polar, and LC-MS lipid) to assess the MS performance, facilitate metabolite identification, and eliminate contamination. Compounds annotation and identification were implemented with commercial software and in-house-developed PAppLineTM and UlibMS library. The batch effects were removed using a deep learning model method (NormAE). Potential biomarkers identification was performed with tree-based modeling algorithms including random forest, AdaBoost, and XGBoost. The modeling performance was evaluated using the F1 score based on a 10-times repeated trial for each. Finally, a sub-cohort case study validated the reliability of the entire workflow.

mmu-lncRNA 121686/hsa-lncRNA 520657 induced by METTL3 drive the progression of AKI by targeting miR-328-5p/HtrA3 signaling axis.

The pathogenesis of acute kidney injury (AKI) is still not fully understood, and effective interventions are lacking. Here, we explored whether methyltransferase 3 (METTL3) was involved in the progression of AKI via regulation of cell death. We reported that PT（proximal tubule）-METTL3-knockout (KO) noticeably suppressed ischemic-induced AKI via inhibition of renal cell apoptosis. Furthermore, we also found that the expression of mmu-long non-coding RNA (lncRNA) 121686 was upregulated in antimycin-treated Boston University mouse proximal tubule (BUMPT) cells and a mouse ischemia-reperfusion (I/R)-induced AKI model. Functionally, mmu-lncRNA 121686 could promote I/R-induced mouse renal cell apoptosis. Mechanistically, mmu-lncRNA 121686 acted as a competing endogenous RNA (ceRNA) to prevent microRNA miR-328-5p-mediated downregulation of high-temperature requirement factor A 3 (Htra3). PT-mmu-lncRNA 121686-KO mice significantly ameliorated the ischemic-induced AKI via the miR-328-5p/HtrA3 axis. In addition, hsa-lncRNA 520657, homologous with lncRNA 121686, sponged miR-328-5p and upregulated Htra3 to promote I/R-induced human renal cell apoptosis. Interestingly, we found that mmu-lncRNA 121686/hsa-lncRNA 520657 upregulation were dependent on METTL3 via N6-methyladenosine (m6A) modification. The mmu-lncRNA 121686/miR-328-5p or hsa-lncRNA 520657/miR-328-5p /HtrA3 axis was induced in vitro by METTL3 overexpression; in contrast, this effect was attenuated by METTL3 small interfering RNA (siRNA). Furthermore, we found that PT-METTL3-KO or METTL3 siRNA significantly suppressed ischemic, septic, and vancomycin-induced AKI via downregulation of the mmu-lncRNA 121686/miR-328-5p/HtrA3 axis. Taken together, our data indicate that the METTL3/mmu-lncRNA 121686/hsa-lncRNA 520657/miR-328-5p/HtrA3 axis potentially acts as a therapeutic target for AKI.

The Core Role of Neutrophil-Lymphocyte Ratio to Predict All-Cause and Cardiovascular Mortality: A Research of the 2005-2014 National Health and Nutrition Examination Survey.

Objective: To further supplement the previous research on the relationship between neutrophil-lymphocyte ratio (NLR) and all-cause and cardiovascular mortality, and construct clinical models to predict mortality. Methods: A total number of 2,827 observers were included from the National Health and Nutrition Examination Survey (NHANES) database in our research. NLR was calculated from complete blood count. According to the quartile of baseline NLR, those observers were divided into four groups. A multivariate weighted Cox regression model was used to analyze the association of NLR with mortality. We constructed simple clinical prognosis models by nomograms. Kaplan-Meier survival curves were used to depict cause-specific mortality. Restricted cubic spline regression was used to make explicit relationships between NLR and mortality. Results: This study recruited 2,827 subjects aged ≥ 18 years from 2005 to 2014. The average age of these observers was 51.55 ± 17.62, and 57.69% were male. NLR is still an independent predictor, adjusted for age, gender, race, drinking, smoking, dyslipidemia, and other laboratory covariates. The area under the receiver operating characteristic curves (AUCs) of NLR for predicting all-cause mortality and cardiovascular mortality were 0.632(95% CI [0599, 0.664]) and 0.653(95% CI [0.581, 0.725]), respectively, which were superior to C-reactive protein (AUCs: 0.609 and 0.533) and WBC (AUCs: 0.522 and 0.513). The calibration and discrimination of the nomograms were validated by calibration plots and concordance index (C-index), and the C-indexes (95% CIs) of nomograms for all-cause and cardiovascular mortality were 0.839[0.819,0.859] and 0.877[0.844,0.910], respectively. The restricted cubic spline showed a non-linear relationship between NLR and mortality. NLR > 2.053 might be a risk factor for mortality. Conclusion: There is a non-linear relationship between NLR and mortality. NLR is an independent factor related to mortality, and NLR > 2.053 will be a risk factor for prognosis. NLR and nomogram should be promoted to medical use for practicality and convenience.

DsbA-L interacts with VDAC1 in mitochondrion-mediated tubular cell apoptosis and contributes to the progression of acute kidney disease.

BACKGROUND: we demonstrated that disulfide-bond A oxidoreductase-like protein (DsbA-L) was involved in the progression of renal fibrosis. However, the precise function of DsbA-L in acute kidney injury (AKI), and the mechanisms involved, have yet to be elucidated. METHODS: We illustrate the DsbA-L interacted with VDAC1 by co-IP (co-immunoprecipitation) in vitro and vivo, and found the interaction parts of them by mutation experiment. The above findings were verified by co-localization of them. In addition, we constructed the two model of PT-DsbA-L and VDAC1 KO mice to verify the function of DsbA-L and VDAC1 in models of VAN, CLP and I/R-induced AKI. FINDINGS: The PT-DsbA-L-KO mice showed amelioration of I/R, VAN-, and CLP-induced AKI progression via the downregulation of VDAC1. Finally, we confirmed these changes in signal molecules by examining in HK-2 cells and kidney biopsies taken from patients with ischemic or acute interstitial nephritis (AIN)-induced AKI. Mechanistically, DsbA-L interacted with amino acids 9-13 and 22-27 of VDAC1 in the mitochondria of BUMPT cells to induce renal cell apoptosis and mitochondrial injury. INTERPRETATION: This work suggested that DsbA-L, located in the proximal tubular cells, drives the progression of AKI, by directly upregulating the levels of VDAC1.Running Title: The role of DsbA-L in AKI FUNDING: National Natural Science Foundation of China, a grant from Key Project of Hunan provincial science and technology innovation, Department of Science and Technology of Hunan Province project of International Cooperation and Exchanges, Changsha Science and Technology Bureau project, Natural Science Foundation of Hunan Province, Fundamental Research Funds for the Central Universities of Central South University, Hunan Provincial Innovation Foundation For Postgraduate China Hunan Provincial Science and Technology Department.

Chemotherapy significantly improves long-term survival of small lesion node negative metaplastic breast carcinoma in T1c population rather than T1a and T1b.

Metaplastic breast carcinoma (MpBC) is considered a highly aggressive disease, the outcome of chemotherapy on small lesions (T1abcN0M0) MpBC patients remain unclear. We identified 890 female MpBC patients in the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2016. After propensity score matching (PSM), 584 patients were matched. Survival probability was compared among T1a, T1b, and T1c patients and between patients with and without chemotherapy using Kaplan-Meier analysis and Cox proportional hazard analysis. Significance was set at two-sided P < 0.05. We classified 49, 166, and 675 patients as T1a, T1b, and T1c MpBC, respectively. The chemotherapy group included 404 patients (45.4%). Following PSM, survival analysis indicated that the patients who underwent chemotherapy had higher OS (P = 0.0002) and BCSS (P = 0.0276) in the T1c substage, but no significant difference was detected in T1a or T1b patients. In this population-based study, small lesion MpBC showed a favorable prognosis. Chemotherapy improved the prognosis of T1c MpBC patients but not T1a and T1b patients to a beneficial extent. Our findings may offer novel insight into a therapeutic strategy for MpBC.

Prognosis Comparison Between Nipple-Sparing Mastectomy and Total Mastectomy in Breast Cancer: A Case-Control Study After Propensity Score Matching.

BACKGROUND: Currently, the operation rate of nipple-sparing mastectomy (NSM) is increasing. However, the long-term prognosis of NSM is not well documented. We utilized the Surveillance, Epidemiology, and End Results (SEER) database to analyze the long-term prognosis of NSM compared with total mastectomy (TM). METHODS: Population-level data of female breast cancer patients treated with NSM and TM were extracted from 1998 to 2016 from the SEER database. Propensity score matching (PSM) was performed to reduce the influence of selection bias and confounding variables in comparisons. Kaplan-Meier analysis, log-rank test, and Cox proportional hazard regression were performed. RESULTS: A total of 5765 patients underwent NSM, which increased from 266 in 2004-2009 to 5370 in 2010-2016. A total of 134,528 patients underwent TM, and the number of patients undergoing TM continued to decline. The overall survival (OS) and breast cancer-specific survival (BCSS) were similar between the NSM group and the TM group (P = 0.058 and 0.87, respectively). For OS, subgroup analysis showed that patients with age ≥ 46, White race, median household income ≥ $70,000, hormone receptor-positive, and HER2 negative had a better prognosis for treatment with NSM. There was no significant difference in BCSS between the NSM group and the TM group. CONCLUSIONS: In recent years, the clinical application of NSM has been increasing. NSM is a proper procedure for breast cancer patients to achieve long-term survival.

Early stage of antibody-mediated rejection after lung transplantation： A case report and literature review. / 肺移植术后早期抗体介导排斥反应1ä¾‹åŠæ–‡çŒ®å¤ä¹ .

Antibody-mediated rejection (AMR) is a rare and serious complication after lung transplantation, with no characteristic of pathological manifestation, no systematic standard treatment, and the poor efficacy and prognosis. We reported a case of early AMR after lung transplantation and the relevant literature has been reviewed. A male patient presented with symptoms of cold 99 days after transplantation and resolved after symptomatic treatment. He admitted to the hospital 14 days later because of a sudden dyspnea and fever. Anti-bacteria, anti-fungi, anti-virus, and anti-pneumocystis carinii treatment were ineffective, and a dose of 1 000 mg methylprednisolone did not work too. The patient's condition deteriorated rapidly and tracheal intubation was done to maintain breathing. Serum panel reactive antibody and donor specific antibody showed postive in humen leukocyte antigen (HLA) II antibody. Pathological examination after transbronchial transplantation lung biopsy showed acute rejection. Clinical AMR was diagnosed combined the donor-specific antibody with the pathological result. The patient was functionally recovered after combined treatment with thymoglobuline, rituximab, plasmapheresis, and immunoglobulin. No chronic lung allograft dysfunction was found after 3 years follow up. We should alert the occurrence of AMR in lung transplantation recipient who admitted to hospital with a sudden dyspnea and fever while showed no effect after common anti-infection and anti-rejection treatment. Transbronchial transplantation lung biopsy and the presence of serum donor-specific antibody are helpful to the diagnosis. The treatment should be preemptive and a comprehensive approach should be adopted.

Prognostic and tumor-immune infiltration cell signatures in tamoxifen-resistant breast cancers.

BACKGROUND: The cumulative risk of distant recurrence of hormone receptor-positive (HR+) breast cancer in the past 20 years has ranged from 22% to 52% after 5 years of endo-therapy. The TNM stage, histological grade, and age are important clinical factors related to recurrence, however the exact mechanism of tamoxifen resistance is still unclear. METHODS: Differentially expressed genes (DEGs) were identified in 10 pairs of patients who had relapsed and non-relapsed after tamoxifen treatment based on matching their clinicopathological factors. After analysis of the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, 10 hub genes were identified using Cytoscape software. Next, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database were used to verify the expression and overall survival (OS) of the 10 hub genes respectively, and GSE96058 and Kaplan-Meier Plotter website were used to further verify the OS of C3, CX3CL1, CXCL2, and SAA1. Finally, Immune Cell Abundance Identifier (ImmuCellAI) and the TIMER database were used to estimate immune cell infiltration and the expression of prognostic genes. RESULTS: The DEGs were mainly enriched in the inflammatory response and cytokine-receptor interaction. The expression and the survival analysis identified CX3CL1, CXCL2, and SAA1 as prognostic factors, whose overexpression in HR+/human epidermal growth factor receptor 2 (HER-2) negative breast cancer possibly predicted a longer disease-free survival. The expression levels of these 3 genes are positively correlated with immune cell infiltration. Their high expression levels may predict longer disease-free survival in breast cancer after tamoxifen treatment and may be biomarkers for tamoxifen-resistant therapy. CONCLUSIONS: In conclusion, the high expression of CX3CL1, CXCL2, and SAA1 may predict longer disease-free survival in breast cancer after tamoxifen treatment and may be a biomarker for tamoxifen therapy.

Formation, contents, functions of exosomes and their potential in lung cancer diagnostics and therapeutics.

Lung cancer is the leading cause of cancer-related death worldwide due to diagnosis in the advanced stage and drug resistance in the subsequent treatments. Development of novel diagnostic and therapeutic methods is urged to improve the disease outcome. Exosomes are nano-sized vehicles which transport different types of biomolecules intercellularly, including DNA, RNA and proteins, and are implicated in cross-talk between cells and their surrounding microenvironment. Tumor-derived exosomes (TEXs) have been revealed to strongly influence the tumor microenvironment, antitumor immunoregulatory activities, tumor progression and metastasis. Potential of TEXs as biomarkers for lung cancer diagnosis, prognosis and treatment prediction is supported by numerous studies. Moreover, exosomes have been proposed to be promising drug carriers. Here, we review the mechanisms of exosomal formation and uptake, the functions of exosomes in carcinogenesis, and potential clinical utility of exosomes as biomarkers, tumor vaccine and drug delivery vehicles in the diagnosis and therapeutics of lung cancer.

A localization-independent approach for invisible and impalpable ground-glass opacity nodules detection in an in vitro lung specimen: two case reports.

A growing number of ground-glass opacity (GGO) nodules are screened out in lungs. Small GGOs are frequently neither visible nor palpable, thus undetectable during operation. Various nodule localization techniques have been developed to facilitate the intraoperative detection of GGO nodules; however, general localization techniques are infeasible or inappropriate in some cases. The detection of small GGO is a great challenge, even within a surgical specimen in the absence of preoperative localization. A localization-independent approach for GGO detection is urgently needed. Herein, we report two cases with invisible and impalpable small GGO which were not appropriate for preoperative localization. The lesions were anatomically resected under the guidance of three-dimensional (3D) reconstruction and got an adequate margin distance. A vessel (artery, vein, or bronchus) which had advanced into or immediately adjacent to the nodule was assigned as a reference vessel. By dissecting and tracing the reference vessel from proximal to distal, the GGO lesions were successfully detected in the surgical specimens, to the eventual obtainment of an accurate pathological diagnosis. Via the two case reports, we introduced an easily handled approach, namely dissecting and tracing a reference vessel, for GGO detection. The novel approach was first described. Combined with precise anatomical segmentectomy guided by 3D reconstruction, it provides an alternative scheme for GGO resection with no need for preoperative localization.

CircRNA_30032 promotes renal fibrosis in UUO model mice via miRNA-96-5p/HBEGF/KRAS axis.

In this study, we investigated the role of circular RNA_30032 (circRNA_30032) in renal fibrosis and the underlying mechanisms. The study was carried out using TGF-ß1-induced BUMPT cells and unilateral ureteral obstruction (UUO)-induced mice, respectively, as in vitro and in vivo models. CircRNA_30032 expression was significantly increased by 9.15- and 16.6-fold on days 3 and 7, respectively, in the renal tissues of UUO model mice. In TGF-ß1-treated BUMPT cells, circRNA_30032 expression was induced by activation of the p38 mitogen-activated protein kinase signaling pathway. Quantitative real-time PCR, western blotting and dual luciferase reporter assays showed that circRNA_30032 mediated TGF-ß1-induced and UUO-induced renal fibrosis by sponging miR-96-5p and increasing the expression of profibrotic proteins, including HBEGF, KRAS, collagen I, collagen III and fibronectin. CircRNA_30032 silencing significantly reduced renal fibrosis in UUO model mice by increasing miR-96-5p levels and decreasing levels of HBEGF and KRAS. These results demonstrate that circRNA_30032 promotes renal fibrosis via the miR-96-5p/HBEGF/KRAS axis and suggest that circRNA_30032 is a potential therapeutic target for treatment of renal fibrosis.

MBD2 Mediates Septic AKI through Activation of PKCη/p38MAPK and the ERK1/2 Axis.

Our previous study demonstrated that the methyl-CpG-binding domain protein 2 (MBD2) mediates vancomycin (VAN)-induced acute kidney injury (AKI). However, the role and regulation of MBD2 in septic AKI are unknown. Herein, MBD2 was induced by lipopolysaccharide (LPS) in Boston University mouse proximal tubules (BUMPTs) and mice. For both in vitro and in vivo experiments, we showed that inhibition of MBD2 by MBD2 small interfering RNA (siRNA) and MBD2-knockout (KO) substantially improved the survival rate and attenuated both LPS and cecal ligation and puncture (CLP)-induced AKI, renal cell apoptosis, and inflammatory factor production. Global genetic expression analyses and in vitro experiments suggest that the expression of protein kinase C eta (PKCη), caused by LPS, is markedly suppressed in MBD2-KO mice and MBD2 siRNA, respectively. Mechanistically, chromatin immunoprecipitation (ChIP) analysis indicates that MBD2 directly binds to promoter region CpG islands of PKCη via suppression of promoter methylation. Furthermore, PKCη siRNA improves the survival rate and attenuates LPS-induced BUMPT cell apoptosis and inflammatory factor production via inactivation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2, which were further verified by PKCη siRNA treatment in CLP-induced AKI. Finally, MBD2-KO mice exhibited CLP-induced renal cell apoptosis and inflammatory factor production by inactivation of PKCη/p38MAPK and ERK1/2 signaling. Taken together, the data indicate that MBD2 mediates septic-induced AKI through the activation of PKCη/p38MAPK and the ERK1/2 axis. MBD2 represents a potential target for treatment of septic AKI.

DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice.

Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.