3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension.

BACKGROUND: Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure. METHODS: Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function. RESULTS: Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments. CONCLUSIONS: 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.

Circular RNAs: emerging players in asthma and COPD.

Circular RNAs (circRNAs) belong to a unique class of endogenously expressed non-protein-coding RNAs with a distinct circularized structure, characterized by the absence of 5'-cap and 3'-polyadenylate ends. They are generally formed through back-splicing from pre-mRNAs. They serve as regulators of transcription and splicing, and act as sponges for microRNAs (miRNAs) and RNA-binding proteins, thereby modulating the expression of target genes. As a result, they exert a substantial impact on a diverse array of cellular and biological processes, including cell proliferation, migration, inflammation, and oxidative stress. Asthma and COPD are chronic airway conditions that currently have no cure. In recent years, emerging evidence suggests that altered expression of circRNAs in airway, bronchial and immune cells is involved in asthma and COPD pathogenesis. Studies exploring circRNA dysregulation in asthma have showcased their involvement in regulating the proliferation, migration, and inflammation of airway smooth muscle and bronchial epithelial cells, as well as impacting goblet cell metaplasia, Th2 cell differentiation, and macrophage activation, primarily through interactions with miRNAs. Similarly, in COPD, circRNAs have shown altered expression patterns in the blood and lungs of patients, and these changes have been linked to modulating inflammation, oxidative stress, and airway remodeling in preclinical models. Furthermore, certain circRNAs have demonstrated promising potential as diagnostic and prognostic biomarkers for both asthma and COPD. This review delves into the current understanding of the function and molecular mechanisms of circRNAs in asthma and COPD, along with exploring their potential as biomarkers in these respiratory conditions.

Emerging role of long non-coding RNA MALAT1 related signaling pathways in the pathogenesis of lung disease.

Long non-coding RNAs (lncRNAs) are endogenously expressed RNAs longer than 200 nt that are not translated into proteins. In general, lncRNAs bind to mRNA, miRNA, DNA, and proteins and regulate gene expression at various cellular and molecular levels, including epigenetics, transcription, post-transcription, translation, and post-translation. LncRNAs play important roles in many biological processes, such as cell proliferation, apoptosis, cell metabolism, angiogenesis, migration, endothelial dysfunction, endothelial-mesenchymal transition, regulation of cell cycle, and cellular differentiation, and have become an important topic of study in genetic research in health and disease due to their close link with the development of various diseases. The exceptional stability, conservation, and abundance of lncRNAs in body fluids, have made them potential biomarkers for a wide range of diseases. LncRNA MALAT1 is one of the best-studied lncRNAs in the pathogenesis of various diseases, including cancers and cardiovascular diseases. A growing body of evidence suggests that aberrant expression of MALAT1 plays a key role in the pathogenesis of lung diseases, including asthma, chronic obstructive pulmonary diseases (COPD), Coronavirus Disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), lung cancers, and pulmonary hypertension through different mechanisms. Here we discuss the roles and molecular mechanisms of MALAT1 in the pathogenesis of these lung diseases.

The emerging diagnostic and therapeutic roles of small nucleolar RNAs in lung diseases.

Small nucleolar RNAs (snoRNAs) are non-coding RNA molecules that range from 60 to 300 nucleotides in length and are primarily located in the nucleoli of cells. They play a critical role in modifying ribosomal RNA and can also regulate alternative splicing and posttranscriptional modification of mRNA. Alterations in snoRNA expression can affect numerous cellular processes, including cell proliferation, apoptosis, angiogenesis, fibrosis, and inflammation, making them a promising target for diagnostics and treatment of various human pathologies. Recent evidence suggests that abnormal snoRNA expression is strongly associated with the development and progression of several lung diseases, such as lung cancer, asthma, chronic obstructive pulmonary disease, and pulmonary hypertension, as well as COVID-19. While few studies have shown a causal relationship between snoRNA expression and disease onset, this research field presents exciting opportunities for identifying new biomarkers and therapeutic targets in lung disease. This review discusses the emerging role and molecular mechanisms of snoRNAs in the pathogenesis of lung diseases, focusing on research opportunities, clinical studies, biomarkers, and therapeutic potential.

Role of Long Non-Coding RNAs in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a debilitating condition of the pulmonary circulatory system that occurs in patients of all ages and if untreated, eventually leads to right heart failure and death. Despite existing medical treatment options that improve survival and quality of life, the disease remains incurable. Thus, there is an urgent need to develop novel therapies to treat this disease. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play critical roles in pulmonary vascular remodeling and PAH. LncRNAs are implicated in pulmonary arterial endothelial dysfunction by modulating endothelial cell proliferation, angiogenesis, endothelial mesenchymal transition, and metabolism. LncRNAs are also involved in inducing different pulmonary arterial vascular smooth muscle cell phenotypes, such as cell proliferation, apoptosis, migration, regulation of the phenotypic switching, and cell cycle. LncRNAs are essential regulators of gene expression that affect various diseases at the chromatin, transcriptional, post-translational, and even post-translational levels. Here, we focus on the role of LncRNAs and their molecular mechanisms in the pathogenesis of PAH. We also discuss the current research challenge and potential biomarker and therapeutic potentials of lncRNAs in PAH.

Improving Right Ventricular Function by Increasing BMP Signaling with FK506.

Right ventricular (RV) function is the predominant determinant of survival in patients with pulmonary arterial hypertension (PAH). In preclinical models, pharmacological activation of BMP (bone morphogenetic protein) signaling with FK506 (tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three patients with end-stage PAH. Whether FK506 has direct effects on the pressure-overloaded right ventricle is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wild-type and heterozygous Bmpr2 mutant mice. RV function and strain were assessed longitudinally via cardiac magnetic resonance imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts and ECs. In mice, low BMP signaling in the right ventricle exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization, and improved RV function and strain over the time course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in human cardiac fibroblasts as a BMPR2 co-receptor to reduce TGFß1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.

Targeted proteomics of right heart adaptation to pulmonary arterial hypertension.

No prior proteomic screening study has centred on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 (discovery cohort) and 76 (validation cohort) PAH patients. The association between proteomic markers and RHMP, defined by the Mayo right heart score (combining RV strain, New York Heart Association (NYHA) class and N-terminal pro-brain natriuretic peptide (NT-proBNP)) and Stanford score (RV end-systolic remodelling index, NYHA class and NT-proBNP), was assessed by partial least squares regression. Biomarker expression was measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatocyte growth factor (HGF), stem cell growth factor-ß, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk of heart failure who warrant closer follow-up and intensified therapy.

Airway Rupture Caused by Double-Lumen Tubes: A Review of 187 Cases.

The double-lumen tubes (DLTs) are the most widely used devices to provide perioperative lung isolation. Airway rupture is a rare but life-threatening complication of DLTs. The primary aim of this review was to collect all cases reported in the literature about airway rupture caused by DLTs and to describe the reported possible contributors, diagnosis, treatment, and outcomes of this complication. Another aim of this review was to assess the possible factors associated with mortality after airway rupture by DLTs. A comprehensive literature search for all cases of airway rupture caused by DLTs was performed in the PubMed, EMBASE, Ovid, Wanfang Database, and CNKI. The extracted data included age, sex, height, weight, type of operation, type and size of DLT, site of airway rupture, possible contributors, clinical presentation, diagnosis timing, treatment, and outcome. We included 105 single case reports and 22 case series with a total number of 187 patients. Most of the ruptures were in the trachea (n = 98, 52.4%) and left main bronchus (n = 70, 37.4%). The common possible contributors include use of a stylet, cuff overdistention, multiple attempts to adjust the position of a DLT, difficult intubation, and use of an oversized DLT. Most of the airway ruptures were diagnosed intraoperatively (n = 138, 82.7%). Pneumomediastinum, air leakage, hypoxemia, and subcutaneous emphysema were the common clinical manifestations. Most patients were treated with surgical repair (n = 147, 78.6%). The mortality of the patients with airway rupture by DLTs was 8.8%. Age, sex, site of rupture, diagnosis timing, and method of treatment were not found to be associated with mortality.

Bioresponsive Nanomedicine: The Next Step of Deadliest Cancers' Theranostics.

Among all cancers, lung, breast, and prostate carcinoma are the three most fatal cancers. Although general therapeutic strategies and existent nanomedicine have been applied in relating cancer treatments, the side effects and potential damage induced by the off-target effect greatly lower the therapeutic efficiency. Recently, an increasing number of bioresponsive nanomaterials is recruited in fighting these deadliest cancers. Therefore, these latest bioresponsive nanomedicine are summarized in the current review. More specifically, the various novel nano-agents that could selectively respond to specific bio-conditions in malignant areas (e.g., pH, temperature, enzyme, Redox, elevated copper ion, etc.) are discussed in detail for their applications in cancer imaging (e.g., fluorescence, NIR, and MRI, etc.) and therapy (e.g., antiangiogenesis, chemotherapy, photothermal, and chemodynamic therapy, etc.). The development of next-generation of bioresponsive nanomedicine and challenges involved are further discussed for future design.

Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of pulmonary artery de-banding.

AIMS: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events. METHODS AND RESULTS: Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)-after RV dysfunction and structural remodelling were established-initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery. CONCLUSION: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events.

Circular RNA CDR1-AS contributes to pemetrexed and cisplatin chemoresistance through EGFR/PI3K signaling pathway in lung adenocarcinoma.

Recent studies found circRNAs were involved in tumorigenesis and became new tumor biomarkers and therapeutic targets in lung adenocarcinoma (LUAD), which played a critical role in various biological processes and had been implicated in resistance to chemotherapeutic drugs. However, the role of CDR1-AS in chemoresistance of LUAD to pemetrexed (PTX) and cisplatin (CDDP) is poorly understood. Here, we found that CDR1-AS was up-regulated in LUAD tissues and cell lines, its high-expression was relevant to smoking history, T stage and neoadjuvant chemotherapy (PTX and CDDP) of LUAD patients. CDR1-AS was an independent prognostic biomarker for LUAD patients. CDR1-AS was highly expressed in PTX and CDDP resistant LUAD tissues and cell line (A549/CR). Silence of CDR1-AS re-sensitized A549/CR cells to PTX and CDDP. CDR1-AS was closely related with EGFR/PI3K signaling pathway in A549/CR cells. The activating of EGFR/PI3K pathway mostly restored the effecting of CDR1-AS silence on PTX and CDDP sensitivity in A549/CR cells, CDR1-AS contributed to PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD. In conclusion, the CDR1-AS is high-expressed in LUAD and is an independent prognostic biomarker for LUAD patients. The high-expression of CDR1-AS is related with the PTX and CDDP insensitivity of LUAD patients, CDR1-AS promotes PTX and CDDP chemoresistance through EGFR/PI3K signaling pathway in LUAD.

Pleomorphic lipoma in the anterior mediastinum: A case report.

BACKGROUND: Pleomorphic lipoma (PL) is a rare benign mesenchymal tumor occurring predominantly in middle-aged and elderly men. It is typically found in the subcutaneous tissue of the posterior neck, back, and shoulders. There have also been a few reported cases in the face, scalp, and upper extremities. Currently, there is no report on its occurrence in the anterior mediastinum. CASE SUMMARY: Herein, we report the case of a 67-year-old woman diagnosed with PL in the anterior mediastinum. The tumor was removed by thoracoscopic surgery. There was no recurrence during the 24-mo follow-up period, and the prognosis was good. Most PL are located on the skin surface. However, they may also occur within the body, even in the mediastinum. CONCLUSION: PL occurring in the anterior mediastinum is rare, and it may be differentiated from other tumors.

Influence of thoracic drainage fluid on proliferation, migration, apoptosis, and drug resistance in lung cancer cell lines.

BACKGROUND: This study aimed to clarify the effect of thoracic drainage fluid (DF) on lung cancer cells in vitro. METHODS: We assessed the influence of DF on the proliferation and migration of lung cancer cells (LTEP-a-2 and A549) using the MTT cell proliferation assay and scratch wound assay. Cell apoptosis was determined by flow cytometric analysis. We also investigated the effect of DF on drug chemosensitivity, assessing viability of LTEP-a-2 and A549 cells. RESULTS: The proliferative rates of cancer cells in the DF-treated group were significantly higher than those of the control group. Similar results were obtained for cell migration of lung cancer cells. Cells in the DF-treated groups showed a lower percentage of apoptosis than those of the control groups. Chemosensitivity of lung cancer cells to doxycycline and cisplatin (DDP) was lowered by DF. CONCLUSION: These findings suggest that DF affects lung cancer cells by promoting proliferation and migration, inhibiting apoptosis, and increasing drug resistance.

The long noncoding RNA ANRIL acts as an oncogene and contributes to paclitaxel resistance of lung adenocarcinoma A549 cells.

Long non-coding RNAs (lncRNAs) are a family of non-protein-coding RNAs that might affect Lung adenocarcinoma (LAD) chemo-resistance and most of them could be used as biomarkers and therapy targets. However, the potential function of lncRNA ANRIL contributed paclitaxel chemo-resistance in LAD is still unknown. This study aimed to observe the expression of ANRIL in LAD, evaluate its biological role in the resistance of LAD cells to paclitaxel and explore the apoptosis role in the ANRIL associated mechanism. Our results showed that ANRIL functioning as a potential oncogene was up-regulated in LAD, and promoted the acquisition of chemo-resistance in paclitaxel partly through the mitochondrial pathway by modulating the expression of apoptosis-related protein cleaved-PARP and Bcl-2. These findings might improve LAD patients' paclitaxel treatment and made ANRIL to be a new target for paclitaxel-based chemotherapy in LAD.

The expression of aplysia ras homolog I (ARHI) and its inhibitory effect on cell biological behavior in esophageal squamous cell carcinoma.

BACKGROUND: Aplysia ras homolog I (ARHI) is a Ras-related maternally imprinted tumor suppressor gene. Loss of ARHI expression contributes to the malignant progression of various tumors. However, reports on the clinical implications and functional role of ARHI expression in esophageal squamous cell carcinoma (ESCC) are limited. This study examined the role of ARHI in ESCC. METHODS: In total, 81 patients diagnosed with ESCC based on histopathological evaluations who were subjected to surgical resection were included in the study. ARHI expression was analyzed by immunohistochemistry and western blotting, examining the correlations between ARHI expression and patient clinicopathological features. The functional effects of ARHI overexpression were examined using a Cell Counting Kit-8 assay, flow cytometry, a Transwell assay, wound healing, and western blotting in the ECA109 cell line. RESULTS: ARHI was highly expressed in 27.5% (22/81) of ESCC specimens (adjacent noncancerous tissues, 85.2%, 69/81; P<0.05). The ARHI expression level was significantly lower in patients with lymph node metastasis than in patients without (P<0.05). A Kaplan-Meier survival analysis showed that patients with low ARHI expression had shorter survival than patients with high expression (P<0.05), and a multivariate Cox analysis revealed that ARHI is an independent predictor of overall survival (P=0.029). Finally, overexpression of ARHI in ESCC cells indicates that ARHI suppresses proliferative capacity, invasive capacity, and cell cycle progression and may also suppress epithelial-mesenchymal transition and induce apoptosis and autophagy. CONCLUSION: ARHI may be a prognostic biomarker and a potential therapeutic target in ESCC.

Elevated fibrous sheath interacting protein 1 levels are associated with poor prognosis in non-small cell lung cancer patients.

In this study, we examined the expression and prognostic value of fibrous sheath interacting protein 1 (FSIP1) in 202 non-small cell lung cancer (NSCLC) patients who underwent lung cancer resection at Shengjing Hospital of China Medical University. FSIP1 mRNA and protein expression were measured in NSCLC tissues and non-tumor adjacent tissues (NATs), and Harrell's concordance index (c-index) was used to evaluate the ability of FSIP1 to predict prognosis. FSIP1 mRNA and protein expression was higher in NSCLC tissues than in NATs. Survival analysis revealed the 5-year overall survival rate to be 35.4% in the FSIP1-positive group and 56.3% in the FSIP1-negative group, and FSIP1-positive status was an independent prognostic factor for poor overall survival. The c-index value of FSIP1 for overall survival was greater than that of Ki67, and the addition of FSIP1 status increased the c-index value of the TNM staging system. These results suggest that evaluating FSIP1 status in addition to TNM stage during routine pathological examinations could improve prognostic predictions in NSCLC patients.