Efficacy and safety of mesenchymal stem cell-derived microvesicles in mouse inflammatory arthritis.

OBJECTIVE: To determine the effective and safe intravenous doses of mesenchymal stem cells (MSCs)-derived microvesicles (MVs) and to elucidate the possible causes of death in mice receiving high-dose MVs. METHODS: MVs were isolated from human MSCs by gradient centrifugation. Mice with collagen-induced arthritis were treated with different doses of intravenous MVs or MSCs. Arthritis severity, white blood cell count, and serum C-reactive protein levels were measured. To assess the safety profile of MSCs and MVs, mice were treated with different doses of MSCs and MVs, and LD50 was calculated. Mouse lungs and heart were assessed by live fluorescence imaging, histopathological measurements, and immunohistochemistry to explore the possible causes of death. Serum concentrations of cTnT, cTnI, and CK-MB were determined by ELISA. With the H9C2 cardiomyocyte cell line,  cellular uptake of MVs was observed using confocal microscopy and cell toxicity was assessed by CCK-8 and flow cytometry. RESULTS: Intravenous treatment with MSCs and MVs alleviated inflammatory arthritis, while high doses of MSCs and MVs were lethal. Mice receiving a maximum dose of MSCs (0.1 mL of MSCs at 109/mL) died immediately, while mice receiving a maximum dose of MVs (0.1 mL of MVs at 1012/mL) exhibited tears, drooling, tachycardia, shortness of breath, unbalanced rollover, bouncing, circular crawling, mania, and death. Some mice died after exhibiting convulsions and other symptoms. All mice died shortly after injecting the maximum dose of MSCs. Histologically, mice receiving high doses of MSCs frequently developed pulmonary embolism, while those receiving high doses of MVs died of myocardial infarction. Consistently, the serum levels of cTnT, cTnI, and CK-MB were significantly increased in the MVs-treated group (P < 0.05). The LD50 of intravenous MVs was 1.60 × 1012/kg. Further, MVs could enter the cell. High doses of MVs induced cell apoptosis, though low concentrations of MVs induced cell proliferation. CONCLUSIONS: Appropriate dosages of MVs and MSCs are effective treatments for inflammatory arthritis while MVs and MSCs overdose is unsafe by causing cardiopulmonary complications.

Feasibility of tracheal reconstruction using silicone-stented aortic allografts.

OBJECTIVES: Tracheal reconstruction post-extensive resection remains an unresolved challenge in thoracic surgery. This study evaluates the use of aortic allografts (AAs) for tracheal replacement and reconstruction in a rat model, aiming to elucidate the underlying mechanisms of tracheal regeneration. METHODS: AAs from female rats were employed for tracheal reconstruction in 36 male rats, with the replacement exceeding half of the tracheal length. To avert collapse, silicone stents were inserted into the AA lumens. No immunosuppressive therapy was administered. The rats were euthanized biweekly, and the AAs were examined for neovascularization, cartilage formation, respiratory epithelial ingrowth, submucosal gland regeneration and the presence of the Sex-determining region of Y-chromosome (SRY) gene. RESULTS: All procedures were successfully completed without severe complications. The AA segments were effectively integrated into the tracheal framework, with seamless distinction at suture lines. Histological analysis indicated an initial inflammatory response, followed by the development of squamous and mucociliary epithelia, new cartilage ring formation and gland regeneration. In situ hybridization identified the presence of the SRY gene in newly formed cartilage rings, confirming that regeneration was driven by recipient cells. CONCLUSIONS: This study demonstrates the feasibility of AAs transforming into functional tracheal conduits, replicating the main structural and functional characteristics of the native trachea. The findings indicate that this approach offers a novel pathway for tissue regeneration and holds potential for treating extensive tracheal injuries.

ncRNAs-mediated TIMELESS overexpression in lung adenocarcinoma correlates with reduced tumor immune cell infiltration and poor prognosis.

Lung adenocarcinoma (LUAD) has a poor prognosis. Circadian genes such as TIMELESS have been associated with several pathologies, including cancer. The expression of TIMELESS and the relationship between TIMELESS, infiltration of tumors and prognosis in LUAD requires further investigation. In this study, we investigated the expression of TIMELESS and its association with survival across several types of human cancer using data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Program. Noncoding RNAs (ncRNAs) regulating overexpression of TIMELESS in lung adenocarcinoma (LUAD) were explored with expression, correlation, and survival analyses. Immune cell infiltration and biomarkers were analyzed between different TIMELESS expression levels. The relationship between TIMELESS expression and immunophenoscores, which were used to predict response to immunotherapy, was evaluated. TIMELESS was identified as a potential oncogene in LUAD. NcRNA analysis showed MIR4435-2HG/hsa-miR-1-3p may interact with TIMELESS in a competitive endogenous RNA network in LUAD tumor tissues. Most immune cells were significantly decreased in TCGA LUAD tumor tissues with high TIMELESS expression except for CD4+T cells and Th2 cells. TIMELESS expression in LUAD tumor tissues was significantly negatively correlated with neutrophil biomarkers, dendritic cell biomarkers (HLA-DPB1, HLA-DQB1, HLA-DRA, HLA-DPA1, CD1C) and an immunophenoscore that predicted outcomes associated with the use of immune checkpoint inhibitors. These findings imply that ncRNAs-mediated TIMELESS overexpression in LUAD tumor tissues correlated with poor prognosis, reduced immune cell infiltration in the tumor microenvironment, and poor response to immune checkpoint inhibitors.

Herbal compound cepharanthine attenuates inflammatory arthritis by blocking macrophage M1 polarization.

OBJECTIVE: Cepharanthine (CEP) is a drug candidate for tumor, viral infection, and some inflammatory diseases, but its effect on rheumatoid arthritis (RA) and the underlying mechanism are incompletely understood. METHODS: CEP was administered intraperitoneally to a collagen-induced arthritis (CIA) model. Joints went radiological and histological examination and serum cytokines were examined with cytometry-based analysis. M1 macrophages were induced from THP-1 cells or mouse bone marrow-derived macrophages with LPS and IFN-γ. Bulk RNA-seq was performed on macrophage undergoing M1-polarizatioin. Western blotting was applied to determine pathways involved in monocyte chemotaxis and polarization. Glycolysis metabolites were measured by chemiluminescence while glycolytic enzymes were examined by quantitative PCR. RESULTS: We found CEP significantly ameliorated synovial inflammation and joint destruction of CIA mice. It downregulated TNF-α levels in serum and in joints. The number of M1 macrophages were reduced in CEP-treated mice. In vitro, CEP inhibited monocyte chemotaxis to MCP-1 by downregulating CCR2 and reducing ERK1/2 signaling. Additionally, CEP suppressed M1 polarization of macrophages induced by LPS and IFN-γ. Genes involved in IFN-γ signaling, IL-6-JAK/STAT3 signaling, glycolysis, and oxidative phosphorylation process were downregulated by CEP. Several enzymes critically involved in glycolytic metabolism were suppressed by CEP, which resulted in reduced citrate in M1-polarizing macrophages. The inhibitory effect of CEP on macrophage polarization might be attributed to the blockage of TLRs-MyD88/IRAK4-IRF5 signaling pathway together with suppression of overactivated glycolytic metabolism in M1-polarizing macrophages. CONCLUSION: CEP attenuated joint inflammation by suppressing monocyte chemotaxis and proinflammatory differentiation. It has the potential to be developed into a complementary or alternative therapy for RA.

A Review of Advances in the Surgical Treatment of Coronary Heart Disease and Lung Cancer.

Lung cancer is currently the most prevalent and fatal malignant tumor in China. Additionally, the incidence of coronary heart disease is steadily increasing. Both diseases exhibit a higher risk of mortality with age, particularly among elderly patients. Moreover, these diseases are interconnected and share common risk factors. However, the treatment options for patients suffering from both lung cancer and coronary heart disease lack clarity and standardized criteria. This article critically examines the literature on surgical interventions for patients with lung cancer complicated by coronary artery disease during the period from January 2021 to December 2022. It summarizes the safety and effectiveness of these interventions and highlights the various surgical options available for different patient profiles.

Advances in mesenchymal stem cell-derived extracellular vesicles therapy for Sjogren's syndrome-related dry eye disease.

Sjogren's syndrome (SS) is a chronic autoimmune disorder that affects exocrine glands, particularly lacrimal glands, leading to dry eye disease (DED). DED is a common ocular surface disease that affects millions of people worldwide, causing discomfort, visual impairment, and even blindness in severe cases. However, there is no definitive cure for DED, and existing treatments primarily relieve symptoms. Consequently, there is an urgent need for innovative therapeutic strategies based on the pathophysiology of DED. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic tool for various autoimmune disorders, including SS-related DED (SS-DED). A particularly intriguing facet of MSCs is their ability to produce extracellular vesicles (EVs), which contain various bioactive components such as proteins, lipids, and nucleic acids. These molecules play a key role in facilitating communication between cells and modulating a wide range of biological processes. Importantly, MSC-derived EVs (MSC-EVs) have therapeutic properties similar to those of their parent cells, including immunomodulatory, anti-inflammatory, and regenerative properties. In addition, MSC-EVs offer several notable advantages over intact MSCs, including lower immunogenicity, reduced risk of tumorigenicity, and greater convenience in terms of storage and transport. In this review, we elucidate the underlying mechanisms of SS-DED and discuss the relevant mechanisms and targets of MSC-EVs in treating SS-DED. In addition, we comprehensively review the broader landscape of EV application in autoimmune and corneal diseases. This review focuses on the efficacy of MSC-EVs in treating SS-DED, a field of study that holds considerable appeal due to its multifaceted regulation of immune responses and regenerative functions.

Tracheal replacement with aortic grafts: Bench to clinical practice.

Tracheal reconstruction following extensive resection for malignant or benign lesions remains a major challenge in thoracic surgery. Numerous studies have attempted to identify the optimal tracheal replacement with different biological or prosthetic materials, such as various homologous and autologous tissues, with no encouraging outcomes. Recently, a few clinical studies reported attaining favorable outcomes using in vitro or stem cell-based airway engineering and also with tracheal allograft implantation following heterotopic revascularization. However, none of the relevant studies offered a standardized technology for airway replacement. In 1997, a novel approach to airway reconstruction was proposed, which involved using aortic grafts as the biological matrix. Studies on animal models reported achieving in-vivo cartilage and epithelial regeneration using this approach. These encouraging results inspired the subsequent application of cryopreserved aortic allografts in humans for the first time. Cryopreserved aortic allografts offered further advantages, such as easy availability in tissue banks and no requirement for immunosuppressive treatments. Currently, stented aortic matrix-based airway replacement has emerged as a standard approach, and its effectiveness was also verified in the recently reported TRITON-01 study. In this context, the present review aims to summarize the current status of the application of aortic grafts in tracheal replacement, including the latest advancements in experimental and clinical practice.

Risk factors for postoperative myasthenia gravis in patients with thymoma without myasthenia gravis: A systematic review and meta-analysis.

Introduction: According to the principle, thymomas combined with myasthenia gravis (MG) require surgical treatment. However, patients with non-MG thymoma rarely develop MG and early- or late-onset MG after surgery is called postoperative MG (PMG). Our study used a meta-analysis to examine the incidence of PMG and risk factors. Methods: Relevant studies were searched for in the PubMed, EMBASE, Web of Science, CNKI,and Wanfang databases. Investigations that directly or indirectly analyzed the risk factors for PMG development in patients with non-MG thymoma were included in this study. Furthermore, risk ratios (RR) with 95% confidence intervals (CI) were pooled using meta-analysis, and fixed-effects or random-effects models were used depending on the heterogeneity of the included studies. Results: Thirteen cohorts containing 2,448 patients that met the inclusion criteria were included. Metaanalysis revealed that the incidence of PMG in preoperative patients with non-MG thymoma was 8%. Preoperative seropositive acetylcholine receptor antibody (AChR-Ab) (RR = 5.53, 95% CI 2.36 - 12.96, P<0.001), open thymectomy (RR =1.84, 95% CI 1.39 - 2.43, P<0.001), non-R0 resection (RR = 1.87, 95% CI 1.36 - 2.54, P<0.001), world health organization (WHO) type B (RR =1.80, 95% CI 1.07 - 3.04, P= 0.028), and postoperative inflammation (RR = 1.63, 95% CI 1.26 - 2.12, P<0.001) were the risk factors for PMG in patients with thymoma. Masaoka stage (P = 0.151) and sex (P = 0.777) were not significantly associated with PMG. Discussion: Patients with thymoma but without MG had a high probability of developing PMG. Although the incidence of PMG was very low, thymectomy could not completely prevent the occurrence of MG. Preoperative seropositive AChR-Ab level, open thymectomy, non-R0 resection, WHO type B, and postoperative inflammation were risk factors for PMG. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022360002.

Applicability Area: A novel utility-based approach for evaluating predictive models, beyond discrimination.

Translating prediction models into practice and supporting clinicians' decision-making demand demonstration of clinical value. Existing approaches to evaluating machine learning models emphasize discriminatory power, which is only a part of the medical decision problem. We propose the Applicability Area (ApAr), a decision-analytic utility-based approach to evaluating predictive models that communicate the range of prior probability and test cutoffs for which the model has positive utility; larger ApArs suggest a broader potential use of the model. We assess ApAr with simulated datasets and with three published medical datasets. ApAr adds value beyond the typical area under the receiver operating characteristic curve (AUROC) metric analysis. As an example, in the diabetes dataset, the top model by ApAr was ranked as the 23rd best model by AUROC. Decision makers looking to adopt and implement models can leverage ApArs to assess if the local range of priors and utilities is within the respective ApArs.

Advancements in innate immune regulation strategies in islet transplantation.

As a newly emerging organ transplantation technique, islet transplantation has shown the advantages of minimal trauma and high safety since it was first carried out. The proposal of the Edmonton protocol, which has been widely applied, was a breakthrough in this method. However, direct contact between islets and portal vein blood will cause a robust innate immune response leading to massive apoptosis of the graft, and macrophages play an essential role in the innate immune response. Therefore, therapeutic strategies targeting macrophages in the innate immune response have become a popular research topic in recent years. This paper will summarize and analyze recent research on strategies for regulating innate immunity, primarily focusing on macrophages, in the field of islet transplantation, including drug therapy, optimization of islet preparation process, islet engineering and Mesenchymal stem cells cotransplantation. We also expounded the heterogeneity, plasticity and activation mechanism of macrophages in islet transplantation, providing a theoretical basis for further research.

Prognostic value of tumor size in thymic epithelial tumors: A systematic review and meta-analysis.

BACKGROUND: Whether the size of thymic epithelial tumors (TETs) has an impact on prognosis has long been a controversial issue. Our study was designed to investigate the value of tumor size in the prognosis (overall survival (OS) and relapse-free survival) of patients with TETs. METHODS: We searched the databases such as PubMed, EMBASE, Web of Science, and clinical trials registration system for articles illustrating the impact of tumor size on survival data in TETs patients. We did a meta-analysis for OS and relapse-free survival. RESULTS: We recruited 9 studies in our meta-analysis. Our study illustrates that TETs patients with small tumor size had better relapse-free survival (hazard ratio = 1.66, 95% confidence interval 1.18-2.35, P = .004) and OS (hazard ratio = 1.93, 95% confidence interval 1.30-2.80, P = .001) in comparison to patients with large tumor size. CONCLUSIONS: In conclusion, the results of our meta-analysis showed that TET size was significantly associated with overall and relapse-free survival of patients, with relatively small tumors tending to have a better prognosis.

The anticancer effects of curcumin and clinical research progress on its effects on esophageal cancer.

Esophageal cancer (EC) is a common tumor of the gastrointestinal system and a major threat to human health. The etiology and incidence of EC vary depending on the type of pathology. Owing to the unique physiological structure of the esophagus and the poor biological behavior of EC, the treatment modalities available are limited, and the prognosis of patients is relatively poor. Curcumin is a type of natural phytochemical belonging to the class of phenolic compounds. It exerts favorable anticancer effects on various cancers. A growing body of evidence indicates that curcumin suppresses tumor development and progression by inhibiting tumor cell proliferation, invasion, and migration, thus inducing apoptosis, regulating microRNA expression, reversing multidrug resistance, and inducing sensitivity to the therapeutic effect of chemoradiotherapy. Multiple cellular molecules, growth factors, and genes encoding proteins participating in different signaling pathways interact with each other to contribute to the complex and orderly anticancer effect. The efficacy and safety of curcumin have been established in preclinical studies for EC and clinical trials for other cancers. However, the low bioavailability of curcumin limits its clinical application. Therefore, the modification of curcumin analogs, the combination of curcumin with other drugs or therapies, and the use of novel nanocarriers have been widely investigated to improve the clinical effects of curcumin in EC.

STAT3 and p63 in the Regulation of Cancer Stemness.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor with many important functions in normal and transformed cells. STAT3 regulatory activities are highly complex as they are involved in various signaling pathways in different cell types under different conditions. Biologically, STAT3 is a regulative factor for normal and cancer stem cells (CSCs). Tumor protein p63 (p63), a member of the p53 protein family, is involved in these biological processes and is also physically and functionally associated with STAT3. STAT3 activation occurs during various aspects of carcinogenesis, including regulation of CSCs properties. In combination with p63, STAT3 is a possible biological marker of CSCs and a major regulator of maintenance of stemness in CSCs. We summarized the STAT3 functions and regulation and its role in CSC properties and highlight how these are affected by its associations with p63.

Learning Curve of Aortic Arch Replacement Surgery in Chinese Mainland with Stanford Type A Aortic Dissection.

BACKGROUND: Stanford type A aortic dissection (TAAD) is the most common cause of death caused by aortic disease in the Chinese mainland. Patients suffering TAAD need immediate surgical treatment [Pompilio 2001; Di Eusanio 2003; Ueda 2003; Li 2013; Afifi 2016; Zhou 2019; Zhou 2021]. Emergency aortic arch replacement is difficult and risky. The prognosis following surgery varies depending on the different surgical approaches [Pompilio 2001; Kazui 2002; Di Eusanio 2003; Ueda 2003; Moon 2009; Li 2013; Afifi 2016; Zhou 2019; Zhou 2021]. Aortic arch replacement includes total-arch replacement (Sun's operation) and hemi-arch replacement. The comparative analysis of learning curves between the two procedures has not been systematically studied. In this study, we studied and analyzed the learning curves of total-arch replacement and hemi-arch replacement using cumulative sum (CUSUM) analysis. METHODS: From January 2013 to December 2019, a total of 139 Stanford TAAD operations were performed by the same surgeon and two assistants, including 61 cases of hemi-arch replacement and 78 cases of total-arch replacement. Baseline information, including preoperative conditions, intraoperative related data and postoperative prognosis, were collected. Descriptive statistics and CUSUM were used to analyze the total operation time, cardiopulmonary bypass (CPB) time, aortic clamping (AC) time, operative mortality, incidence of postoperative complications, postoperative intensive care unit (ICU) time, hospital stay, and postoperative drainage volume. RESULTS: A total of 139 patients with TAAD (age 48.8 ± 12.3, male, 107, female, 32) underwent emergency aortic arch replacement. A total of 61 patients (43.9%) underwent hemi-arch replacement, and 78 patients (56.1%) underwent total-arch replacement. The total time, cardiopulmonary bypass (CPB) time, and aortic clamping (AC) time of hemi-arch operation were 434.2 ± 137.0 minutes, 243.3 ± 87.2 minutes, and 157.0 ± 60.2 minutes. The total, CPB, and AC times of total-arch operation were 747.8 ± 164.3 minutes, 476.4 ± 121.6 minutes, and 238.5 ± 67.6 minutes. The mortality of hemi-arch operation was 3.3%, and that of total-arch operation was 6.4%. The incidence of complications after hemi-arch operation was 11.3%, and that after total-arch operation was 46.2%. The ICU time and hospital stay after hemi-arch surgery were 7.3 ± 4.4 days and 27.2 ± 16.2 days, respectively, and the ICU time and total hospital stay after total-arch surgery were 7.2 ± 5.9 days and 24.0 ± 10.3 days, respectively. The total drainage volume after hemi-arch operation was 2182.4 ± 1236.4 ml, and that after total-arch operation was 2467.3 ± 1385.7 ml. According to CUSUM analysis, the same cardiovascular surgery team seems to have different learning curves in the time of two operations. CUSUM analysis of intraoperative and postoperative indicators shows that after a certain period of professional and systematic cardiovascular surgery training, aortic hemi-arch replacement has the characteristics of short learning cycle and easy to master for surgeons, while total-arch replacement requires a longer learning cycle. CONCLUSIONS: Although the emergency operation of TAAD is difficult and risky, according to results the of CUSUM analysis, cardiovascular surgeons can achieve better learning results in hemi-arch replacement than total-arch replacement.

Bioinformatic-based Identification of Genes Associated with Aortic Valve Stenosis.

BACKGROUND: Aortic valve stenosis (AS) disease is the most common valvular disease in developed countries. The pathology of AS is complex, and its main processes include calcification of the valve stroma and involve genetic factors, lipoprotein deposition and oxidation, chronic inflammation, osteogenic transition of cardiac valve interstitial cells, and active valve calcification. The aim of this study was to identify potential genes associated with AS. METHODS: Three original gene expression profiles (GSE153555, GSE12644, and GSE51472) were downloaded from the Gene Expression Omnibus (GEO) database and analyzed by GEO2R tool or 'limma' in R to identify differentially expressed genes (DEGs). Functional enrichment was analyzed using the ClusterProfiler package in R Bioconductor. STRING was utilized for the Protein-Protein Interaction (PPI) Network construct, and tissue-specific gene expression were identified using BioGPS database. The hub genes were screened out using the Cytoscape software. Related miRNAs were predicted in Targetscan, miWalk, miRDB, Hoctar, and TarBase. RESULTS: A total of 58 upregulated genes and 20 downregulated genes were screened out, which were mostly enriched in matrix remodeling and the immune system process. A module was thus clustered into by PPI network analysis, which mainly involved in Fc gamma R-mediated phagocytosis, Osteoclast differentiation. Ten genes (IBSP, NCAM1, MMP9, FCGR3B, COL4A3, FCGR1A, THY1, RUNX2, ITGA4, and COL10A1) with the highest degree scores were subsequently identified as the hub genes for AS by applying the CytoHubba plugin. And hsa-miR-1276 was finally identified as potential miRNA and miRNA-gene regulatory network was constructed using NetworkAnalyst. CONCLUSIONS: Our analysis suggested that IBSP, NCAM1, MMP9, FCGR3B, COL4A3, FCGR1A, THY1, RUNX2, ITGA4, and COL10A1 might be hub genes associated with AS, and hsa-miR-1276 was potential miRNA. This result could provide novel insight into pathology and therapy of AS in the future.

COL8A1 Promotes NSCLC Progression Through IFIT1/IFIT3-Mediated EGFR Activation.

Activation of EGFR is a major risk factor for non-small cell lung cancer (NSCLC). Understanding the molecular events promoting EGFR activation can help us gain more insights into the progression of NSCLC. In this study, we demonstrate that collagen type VIII alpha 1 chain (COL8A1), an extracellular matrix component, was overexpressed in NSCLC. In NSCLC cells, knockdown of COL8A1 suppressed cell growth, cycle progression, and migration, and induced cell apoptosis. While COL8A1 overexpression promoted cell proliferation and inhibited cell apoptosis. In addition, we found that COL8A1 depletion reduced interferon response signaling and downregulated (IFIT1) and interferon-induced proteins with tetratricopeptide repeats 3 (IFIT3). Moreover, we indicated that COL8A1 could upregulate IFIT1 and IFIT3 mediated EGFR activation in vitro and in vivo. Lastly, there was a positive correlation among COL8A1, IFIT1, and IFIT3 expression, and EGFR activity in patients with NSCLC. Overall, our data demonstrate that COL8A1 contributes to NSCLC proliferation and invasion through EGFR activation, dependent on IFIT1 and IFIT3 expression.