Potential biomarkers for diagnosis and disease evaluation of idiopathic pulmonary fibrosis.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by progressive lung fibrogenesis and histological features of usual interstitial pneumonia. IPF has a poor prognosis and presents a spectrum of disease courses ranging from slow evolving disease to rapid deterioration; thus, a differential diagnosis remains challenging. Several biomarkers have been identified to achieve a differential diagnosis; however, comprehensive reviews are lacking. This review summarizes over 100 biomarkers which can be divided into six categories according to their functions: differentially expressed biomarkers in the IPF compared to healthy controls; biomarkers distinguishing IPF from other types of interstitial lung disease; biomarkers differentiating acute exacerbation of IPF from stable disease; biomarkers predicting disease progression; biomarkers related to disease severity; and biomarkers related to treatment. Specimen used for the diagnosis of IPF included serum, bronchoalveolar lavage fluid, lung tissue, and sputum. IPF-specific biomarkers are of great clinical value for the differential diagnosis of IPF. Currently, the physiological measurements used to evaluate the occurrence of acute exacerbation, disease progression, and disease severity have limitations. Combining physiological measurements with biomarkers may increase the accuracy and sensitivity of diagnosis and disease evaluation of IPF. Most biomarkers described in this review are not routinely used in clinical practice. Future large-scale multicenter studies are required to design and validate suitable biomarker panels that have diagnostic utility for IPF.

LncRNA GSCAR promotes glioma stem cell maintenance via stabilizing SOX2 expression.

Gliomas are the most aggressive type of malignant brain tumors. Recent studies have demonstrated that the existence of glioma stem cells (GSCs) is critical for glioma recurrence, metastasis, and chemo- or radio-therapy resistance. Temozolomide (TMZ) has been used as an initial therapy for gliomas. However, the overall survival time is still limiting due to the lack of effective targets and treatment options. Therefore, identifying novel biomarkers for gliomas, especially for GSCs, is important to improve the clinical outcome in the future. In this study, we identify a human-specific long non-coding RNA (lncRNA, ENSG00000250377), termed GSCAR (glioma stem cell associated lncRNA), which is highly expressed in glioma cancerous tissues and cell lines. We reveal that GSCAR positively correlates with tumor grade. Glioma patients with GSCAR high expression exhibit shortened overall survival time, compared to patients with GSCAR low expression. Furthermore, we show that GSCAR knockdown by shRNAs or antisense oligonucleotide (ASO) reduces tumor cell proliferation, migration and xenograft tumor formation abilities. Mechanistic study shows that GSCAR acts as a ceRNA (competing endogenous RNA) for miR-6760-5p to promote the expression of oncogene SRSF1 (serine and arginine rich splicing factor 1). In addition, GSCAR mediates the protein complex formation between DHX9 (DExH-Box helicase 9) and IGF2BP2 (insulin-like growth factor 2 mRNA-binding protein 2), leading to the stabilization of SOX2 (sex-determining region Y-box 2) mRNA and then the transcriptional activation of GSCAR. Depleting GSCAR reduces SOX2 expression and GSC self-renewal ability, but promotes tumor cell responses to TMZ. These findings uncover that GSCAR/miR-6760-5p/SRSF1 axis and GSCAR/DHX9-IGF2BP2/SOX2 positive feedback loop are critical for glioma progression, which could be used as prognostic biomarkers and therapeutic targets in the future.

Progress in the Clinical Assessment and Treatment of Myocardial Depression in Critically Ill Patient with Sepsis.

Myocardial inhibition is the main cause of death in patients with sepsis.In recent years, methodological differences in the diagnosis, assessment, and treatment of septic myocardial depression have been observed, and how to objectively and accurately evaluate the degree of myocardial depression and the timing of treatment strategies have generally been the focus of this area of research. Based on the relevant research at home and abroad, the current review summarizes the clinical characteristics, methodological diagnosis, and symptomatic treatment of septic myocardial depression. The aim of doing so is to provide a reference for the early identification and treatment of patients with sepsis and myocardial depression.

LncRNA-AC068228.1 Is a Novel Prognostic Biomarker That Promotes Malignant Phenotypes in Lung Adenocarcinoma.

Background: The crucial roles played by lncRNA-AC068228.1 in primary malignant cancer remain poorly understood. This study aimed at examining the clinical significance and evaluating the biological function of AC068228.1 in lung adenocarcinoma (LUAD). Methods: We used data obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and the Gene Expression Omnibus (GEO) database to examine the expression of AC068228.1 in LUAD patients, and the prognostic and diagnostic value of those levels. Functional experiments were conducted to determine the function of AC068228.1 on LUAD cells. Signaling pathway enrichment analysis of AC068228.1 was conducted using the clusterProfiler and Gene Set Enrichment Analysis (GSEA) software. We analyzed the correlation between AC068228.1 expression and immune infiltration level in LUAD using the single-sample gene set enrichment analysis (ssGSEA) method by the R package GSVA. Results: AC068228.1 expression was significantly elevated in LUAD tissues compared with normal tissues. Higher expression of AC068228.1 was strongly correlated with adverse clinical outcomes and was identified as an independent prognostic marker for LUAD patients. GSEA and infiltration analysis confirmed that AC068228.1 expression was significantly correlated with immune cells infiltrating in LUAD. Knockdown of AC068228.1 inhibited the cell proliferation and cell migration of LUAD. Conclusions: AC068228.1 was upregulated in LUAD and was significantly correlated with adverse clinical outcomes. Meanwhile, it was associated with immune cell infiltration and could be used as a promising diagnostic and prognostic biomarker for LUAD patients.

Atrial fibrillation and concomitant left subclavian, axillary and brachial artery embolism after fiberoptic bronchoscopy: A case report.

BACKGROUND: Fiberoptic bronchoscopy has been widely used in the diagnosis and treatment of respiratory diseases. Numerous major and minor complications have been reported following this procedure. The incidence of major postoperative complications is approximately 0.5% and includes respiratory depression, pneumothorax, pulmonary edema, pneumonia, airway obstruction and cardiorespiratory arrest. Minor complications include vasovagal reactions, cardiac arrhythmias, hemorrhage, pneumothorax, aphonia, nausea, vomiting and fever. However, to our knowledge, a case of atrial fibrillation (AF) concomitant with fatal arterial embolism in the upper extremities following diagnostic bronchoscopy has never been reported. CASE SUMMARY: A 70-year-old female patient presented with a history of rheumatic heart disease beginning at 10 years of age and an approximately 10-year history of hypertension. The patient was transferred from the cardiology department to the respiratory department due to recurrent coughing, pneumonia, and fever. She underwent fiberoptic bronchoscopy in the respiratory department. Approximately 2 h after completion of bronchoscopy, she complained of left arm numbness and weakness. Physical examination detected cyanosis of the left upper extremity, grade III weakened limb muscle strength, and undetectable left brachial artery pulsation. Auscultation indicated AF. B-mode ultrasound examination of the blood vessels showed hyperechoic material in the left subclavian, axillary and brachial arteries, and parallel veins. As our hospital has no vascular surgery capability, the patient was transferred to a specialized hospital for emergency thrombectomy that day. A tracking investigation found that the patient's conditions improved after successful thrombectomy. CONCLUSION: Thromboembolism following bronchoscopy is rare, and only a few cases of cerebral air embolism after bronchoscopy have been reported.

The role of m6A modification in the biological functions and diseases.

N6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as "readers". Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

Role of various imbalances centered on alveolar epithelial cell/fibroblast apoptosis imbalance in the pathogenesis of idiopathic pulmonary fibrosis.

ABSTRACT: There have been recent extensive studies and rapid advancement on the pathogenesis underlying idiopathic pulmonary fibrosis (IPF), and intricate pathogenesis of IPF has been suggested. The purpose of this study was to clarify the logical relationship between these mechanisms. An extensive search was undertaken of the PubMed using the following keywords: "etiology," "pathogenesis," "alveolar epithelial cell (AEC)," "fibroblast," "lymphocyte," "macrophage," "epigenomics," "histone," acetylation," "methylation," "endoplasmic reticulum stress," "mitochondrial dysfunction," "telomerase," "proteases," "plasminogen," "epithelial-mesenchymal transition," "oxidative stress," "inflammation," "apoptosis," and "idiopathic pulmonary fibrosis." This search covered relevant research articles published up to April 30, 2020. Original articles, reviews, and other articles were searched and reviewed for content; 240 highly relevant studies were obtained after screening. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors: environmental exposures affect epigenetic marks; epigenetic processes translate environmental exposures into the regulation of chromatin; epigenetic processes shape gene expression profiles; in turn, an individual's genetic background determines epigenetic marks; finally, these genetic and epigenetic factors act in concert to dysregulate gene expression in IPF lung tissue. The pathogenesis of IPF involves various imbalances including endoplasmic reticulum, telomere length homeostasis, mitochondrial dysfunction, oxidant/antioxidant imbalance, Th1/Th2 imbalance, M1-M2 polarization of macrophages, protease/antiprotease imbalance, and plasminogen activation/inhibition imbalance. These affect each other, promote each other, and ultimately promote AEC/fibroblast apoptosis imbalance directly or indirectly. Excessive AEC apoptosis and impaired apoptosis of fibroblasts contribute to fibrosis. IPF is likely the result of complex interactions between environmental, genetic, and epigenetic factors. The pathogenesis of IPF involves various imbalances centered on AEC/fibroblast apoptosis imbalance.

Bone marrow stem cells therapy alleviates vascular injury in a chronic obstructive pulmonary disease­obstructive sleep apnea overlap syndrome rat model.

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are highly prevalent potential risk factors for systemic disease. Previous studies have reported that COPD and OSA are major independent risk factors for cardio­ or cerebrovascular diseases. The present study aimed to investigate the role of bone marrow mesenchymal stem cells (BMSCs) on vascular injury in a COPD­OSA overlap syndrome (OS) rat model. Rats were randomly divided into three groups: Sham, OS model and BMSC. BMSC localization in major organs was detected via confocal laser fluorescence microscopy, and the aortic tissue pathological changes and related genes were measured using hematoxylin & eosin and Masson staining. Genes associated with vascular endothelial cell injury, including endothelin 1, vascular cell adhesion molecule 1 and endothelial nitric oxide synthase, were detected via reverse transcription­quantitative PCR and western blotting. Apoptosis of vascular endothelial cells was detected using TUNEL and immunofluorescence assays. The endothelial cell marker CD31 in injured vessels was analyzed via immunohistochemistry. BMSCs migrated into the heart, liver, spleen, lung, kidney, brain and aorta in the OS model. The green fluorescence expression of BMSCs demonstrated the highest level in the lung, followed by the aorta. Aortic tissue had a more severe vascular injury and increased apoptosis in the model group compared with the BMSC group. Vascular endothelial cell apoptosis was decreased in the BMSC group compared with the model group. The findings suggested that BMSCs could repair vascular injury by inhibiting endothelial cell damage and apoptosis. These data provide a theoretical basis for the treatment of cardiovascular diseases caused by OS with BMSCs.

Diagnosis of complication in lung transplantation by TBLB + ROSE + mNGS.

Lung transplantation is a potentially life-saving therapy for patients with terminal respiratory illnesses. Long-term survival is limited by the development of a variety of opportunistic infections and rejection. Optimal means of differential diagnosis of infection and rejection have not been established. With these challenges in mind, we tried to use transbronchial lung biopsy (TBLB) rapid on-site cytological evaluation (ROSE), metagenomic next-generation sequencing (mNGS), and routine histologic examination to timely distinguish infection and rejection, and accurately detect etiologic pathogens. We reviewed the medical records of all patients diagnosed with infection or rejection by these means from December 2017 to September 2018 in our center. We identified seven recipients whose clinical course was complicated by infection or rejection. Three patients were diagnosed with acute rejection, organizing pneumonia, and acute fibrinoid organizing pneumonia, respectively. Four of the seven patients were diagnosed with infections, including Pneumocystis carinii pneumonia, cytomegalovirus, Aspergillus, and bacterial pneumonia. These patients recovered after proper treatment. TBLB + ROSE + mNGS might be a good method to accurately detect etiologic pathogens, which may help us to facilitate the use of targeted and precision medicine therapy in postoperative complications and avoid unnecessary potential adverse effects of drugs.

Optimal specimen type for accurate diagnosis of infectious peripheral pulmonary lesions by mNGS.

BACKGROUND: Reports on the application of metagenomic next-generation sequencing (mNGS) to the diagnosis of peripheral pulmonary lesions (PPLs) are scarce. There have been no studies investigating the optimal specimen type for mNGS. METHODS: We used mNGS to detect pathogens in matched transbronchial lung biopsy (TBLB), bronchoalveolar lavage fluid (BALF), and bronchial needle brushing (BB) specimens from 39 patients suspected of having infectious PPLs. We explored differences in microbial composition and diagnostic accuracy of mNGS for the 3 specimen types. RESULTS: mNGS was more sensitive than conventional culture for detection of bacteria and fungi in TBLB, BALF, and BB specimens, with no difference in the sensitivity of mNGS across the different specimen types. mNGS showed higher sensitivity for fungi or uncategorized pulmonary pathogens in TBLB+BALF+BB compared to TBLB but not BALF or BB specimens. There were no significant differences between the 3 specimen types in the relative abundance of pathogens, or between TBLB and BB specimens in the relative abundance of 6 common lower respiratory tract commensals. CONCLUSIONS: mNGS has a higher sensitivity than the conventional culture method for detecting pathogens in TBLB, BALF, or BB specimens. mNGS of BB samples is a less invasive alternative to TBLB for the diagnosis of infectious PPLs.

Effects of bone marrow­derived mesenchymal stem cell transplantation on chronic obstructive pulmonary disease/obstructive sleep apnea overlap syndrome in rats.

Bone marrow­derived mesenchymal stem cells (BMSCs) possess potential therapeutic properties for treating patients with chronic obstructive pulmonary disease (COPD), which is characterized by emphysema and obstructive sleep apnea (OSA). However, their effects on overlap syndrome (OS) remain unclear. We investigated the potential therapeutic effects and possible mechanisms of BMSC transplantation in OS rats. To generate the OS model in rats, the animals underwent daily exposure to cigarette smoke and intermittent hypoxia. BMSCs were intravenously injected into rats. At 4 weeks post­transplantation, the severity of emphysema was assessed by lung hematoxylin and eosin (H&E) staining. The levels of oxidative stress and the malondialdehyde (MDA) and superoxide dismutase (SOD) contents in serum and lung were detected. The apoptosis of alveolar septal cells was also detected by TUNEL assay. Finally, we determined the expression of CD31 and VWF in lung tissues by an immunohistochemical (IHC) assay. It was found that BMSCs were able to migrate to the injured lung and aorta tissues. In lung tissues, transplanted BMSCs, some of which had differentiated into endotheliocytes, were found in the alveolar walls. The mean linear intercept (MLI) and pathological scores were higher and the mean alveolar number (MAN) was lower in the OS group than these parameters in the control group. These values were significantly reduced in the OS+BMSC group compared to those in the OS group. The MDA content was decreased and SOD activity was increased in the OS+BMSC group compared to those in the OS group. The apoptotic index of alveolar wall cells in the OS group was higher than that in the OS+BMSC group. The expression levels of CD31 and VWF in alveolar wall cells in the OS group were lower than those in the OS+BMSC group. These results indicate that BMSCs may inhibit the progression of emphysema in the OS model by differentiating into endotheliocytes and suppressing the apoptosis of endotheliocytes and oxidative stress. There is a possibility that the release of growth factors and structural support may be a determinant for the regenerative effects observed following treatment with BMSCs.

Comparison of chemical stability and corrosion resistance of group IV metal oxide films formed by thermal and plasma-enhanced atomic layer deposition.

The wide applications of ultrathin group IV metal oxide films (TiO2, ZrO2 and HfO2) probably expose materials to potentially reactive etchants and solvents, appealing for extraordinary chemical stability and corrosion resistance property. In this paper, TiO2 ultrathin films were deposited on Si at 200 °C while ZrO2 and HfO2 were grown at 250 °C to fit their growth temperature window, by thermal atomic layer deposition (TALD) and plasma-enhanced ALD (PEALD). A variety of chemical liquid media including 1 mol/L H2SO4, 1 mol/L HCl, 1 mol/L KOH, 1 mol/L KCl, and 18 MΩ deionized water were used to test and compare chemical stability of all these as-deposited group IV metal oxides thin films, as well as post-annealed samples at various temperatures. Among these metal oxides, TALD/PEALD HfO2 ultrathin films exhibit the best chemical stability and anti-corrosion property without any change in thickness after long time immersion into acidic, alkaline and neutral solutions. As-deposited TALD ZrO2 ultrathin films have slow etch rate of 1.06 nm/day in 1 mol/L HCl, however other PEALD ZrO2 ultrathin films and annealed TALD ones show better anti-acid stability, indicating the role of introduction of plasma O2 in PEALD and post-thermal treatment. As-deposited TiO2 ultrathin films by TALD and PEALD are found to be etched slowly in acidic solutions, but the PEALD can decrease the etching rate of TiO2 by ~41%. After post-annealing, TiO2 ultrathin films have satisfactory corrosion resistance, which is ascribed to the crystallization transition from amorphous to anatase phase and the formation of 5% Si-doped TiO2 ultrathin layers on sample surfaces, i.e. Ti-silicate. ZrO2, and TiO2 ultrathin films show excellent corrosion endurance property in basic and neutral solutions. Simultaneously, 304 stainless steel coated with PEALD-HfO2 is found to have a lower corrosion rate than that with TALD-HfO2 by means of electrochemical measurement. The pre-treatment of plasma H2 to 304 stainless steel can effectively reduce interfacial impurities and porosity of overlayers with significantly enhanced corrosion endurance. Above all, the chemical stability and anti-corrosion properties of IV group metal oxide coatings can be improved by using PEALD technique, post-annealing process and plasma H2 pre-treatment to substrates.

[Effects and possible mechanisms of mesenchymal stem cell transplantation on emphysema in rats].

OBJECTIVE: To explore the effects of transplanting bone marrow mesenehymal stem cells (MSCs) on emphysema in rats and elucidate the possible mechanisms. METHODS: A total of 24 female Sprague-Dawley rats were randomly divided randomly into 3 groups of control, emphysema and MSCs transplantation (n=8 each). The rat model of emphysema was established by 14-week exposure to cigarette smoking and then MSCs labeled with 4, 6-diamidino-2-phenylindole (DAPI) were injected into recipient rats of MSCs transplantation group via tail veins. At 2 and 4 weeks post-transplantation, engraftment and differentiation of MSCs was determined. At 8 weeks post-transplantation, lung fissure sections were prepared for examining the morphological alterations. The apoptosis of alveolar septal cells was assessed. And the levels of oxidative stress in sera and lung were detected. RESULTS: At 2 and 4 weeks post-transplantation, MSCs labeled with DAPI could be found in recipient lungs, some of which differentiated into type II alveolar epithelial cells. Mean linear intercept was higher in emphysema and MSCs transplantation groups than control group [(111 ± 23) and (90 ± 15) vs (74 ± 10) µm], mean alveolar numbers were lower than control group [(94 ± 22) and (125 ± 15) vs (159 ± 22)/mm²] (all P<0.05); mean linear intercept was higher and mean alveolar numbers were lower in emphysema group than MSCs transplantation group (both P<0.05). The apoptotic index of alveolar wall cells in emphysema group was higher than MSCs transplantation group [(13.5 ± 2.5)% vs (4.8 ± 0.7)%, P<0.05]. Malondialdehyde of sera and lung in emphysema and MSCs transplantation groups was higher than control group [(4.3 ± 0.8), (3.7 ± 0.4) vs (3.0 ± 0.4) nmol/ml, (5.4 ± 0.5), (4.8 ± 0.4) vs (4.2 ± 0.6) nmol/mg, all P<0.05]; malondialdehyde of sera and lung in emphysema group was higher than MSCs transplantation group (both P<0.05). Superoxide dismutase (SOD) of sera and lung in emphysema and MSCs transplantation groups was lower than control group [(8.7 ± 0.8), (9.6 ± 0.7) vs (10.5 ± 0.9) U/ml and (56.3 ± 13.4), (70.2 ± 11.0) vs (84.9 ± 13.0) U/mg, all P<0.05]; SOD of sera and lung in emphysema group was lower than MSCs transplantation group (both P<0.05). CONCLUSION: MSCs transplantation via tail vein may arrest the progression of emphysema in a cigarette-smoke-induced rat model of emphysema through a differentiation of injected MSCs into type II alveolar epithelial cells and down-regulations of apoptosis and oxidative stress.

Biological effects and mechanisms of action of mesenchymal stem cell therapy in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is the most frequent chronic respiratory disease and a leading cause of morbidity and mortality, worldwide. Given that the foremost risk factor leading to the development of COPD is cigarette smoke, the initial treatment for COPD is smoking cessation. Even after smoking cessation, inflammation, apoptosis and oxidative stress can persist and continue to contribute to COPD. Although current therapies for COPD (which are primarily based on anti-inflammatory drugs such as corticosteroids, theophylline and bronchodilators) reduce airway obstruction, limit COPD exacerbation and improve the patient's health-related quality-of-life, none can prevent disease progression or reduce mortality. Recent advances in stem cell research have provided novel insight into the potential of bone marrow mesenchymal stem cells (MSCs) in the treatment of several pulmonary diseases. This review article discusses the biological effects and mechanisms of action of MSC transplantation in COPD, and highlights the foundation that MSCs provide for novel therapeutic approaches in COPD.