Diagnostic Potential of Serum Glycome Analysis in Lung Cancer: A Glycopattern Study.

Lung cancer is the leading cause of cancer-related death, with high morbidity and mortality rates due to the lack of reliable methods for diagnosing lung cancer at an early stage. Low-dose computed tomography can help detect abnormal areas in the lungs, but only 16% of cases are diagnosed early. Tests for lung cancer markers are often employed to determine genetic expression or mutations in lung carcinogenesis. Serum glycome analysis is a promising new method for early lung cancer diagnosis as glycopatterns exhibit significant differences in lung cancer patients. In this study, we employed a solid-phase chemoenzymatic method to systematically compare glycopatterns in benign cases, adenocarcinoma before and after surgery, and advanced stages of adenocarcinoma. Our findings indicate that serum high-mannose levels are elevated in both benign cases and adenocarcinoma, while complex N-glycans, including fucose and 2,6-linked sialic acid, are downregulated in the serum. Subsequently, we developed an algorithm that utilizes 16 altered N-glycans, 7 upregulated and 9 downregulated, to generate a score based on their intensity. This score can predict the stages of cancer progression in patients through glycan characterization. This methodology offers a potential means of diagnosing lung cancer through serum glycome analysis.

Plasma neuron specific enolase (NSE), tumour necrosis factor-alpha (TNF-α) and soluble IL-2 receptor alpha (sIL-2Rα) levels in children with developmental delay (DD): Use of combined ROC curves to increase their diagnostic value.

BACKGROUND: Developmental delay (DD) occurs when children fail to reach developmental milestones in comparison to peers of the same age range. However, there are no valuable biomarkers for the early diagnosis of DD. Since there is no specific marker for screening the disease, we evaluated plasma NSE, TNF-α and sIL2-Rα as potential markers for this purpose. METHODS: In this cross-sectional randomized case-control study, a total of 174 DD patients and 49 matched elderly controls aged between 2 months and 60 months were recruited. A sensitive enzyme-linked immunosorbent assay and an immunoradiometric assay were used to evaluate the levels of plasma IL-1, IL-6, IL-8, IL-10, sIL2-Rα, TNF-α, and NSE. Statistical analyses using t test, χ2, ANOVA, ROC curves and binary logistic regression models were performed. RESULTS: In comparison to the control group, the DD group had greater levels of NSE, TNF-α, and sIL2-Rα(p < 0.05). In the binary logistic regression analysis of DD, NSE had an odds ratio (OR) of 1.783 (95 % CI 1.297 to 2.451, p = 0.000), indicating that NSE was an independent risk factor for DD. The plasma TNF-α level was positively correlated with plasma NSE and sIL2-Rα levels in the DD group (r = 0.366 and 0.433, respectively), and the DQ score and plasma sIL2-Rα level in the DD group were positively correlated. The ROC curve revealed that the respective areas under the NSE, TNF-α, and sIL2-Rα ROC curves were 0.9797, 0.9365, and 0.8533, respectively. Moreover, a significant increase in AUC was observed using combined ROC curve analysis. CONCLUSIONS: Children with DD have significantly altered plasma concentrations of sIL2-Rα, NSE, and TNF-α. NSE, TNF-α and sIL2-Rα can be used as DD blood biomarkers. This information may be helpful in early diagnosis and intervention.

Urine-Derived Stem Cells Reverse Bleomycin­Induced Experimental Pulmonary Fibrosis by Inhibition of the TGF-ß1-Smad2/3 Pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung interstitial lesions with the disease pathophysiology incompletely understood, which is a serious and fatal disorder with limited treatment options. Mesenchymal stem cells (MSCs) have exhibited promising therapeutic capability for IPF. While most types of MSCs are obtained invasively, urine-derived stem cells (USCs) can be gained in a safe, noninvasive, and inexpensive procedure, which are readily available and reported to exhibit no risk of teratoma formation or oncogenic potential in vivo, sounding alternative to other MSCs. This study aims to investigate the therapeutic effect and mechanism of USCs on IPF, using a bleomycin (BLM)-induced IPF model in mice. METHODS: Cell surface marker examination by flow cytometry analysis and cell differentiation culture were used to characterize USCs obtained from healthy individuals. BLM was instilled endotracheally in adult C57BL/6 mice, followed by USCs or human bone marrow-derived mesenchymal stem cells (BMSCs) treatment by tail vein injection on day 14. Mice were euthanized on day 14 before administration or day 21 for the evaluation of pulmonary histopathology and hydroxyproline (HYP) content. Inflammatory factors of the lung, including transforming growth factor (TGF)-ß1, TNF-α, IL-6, MMP2 were analyzed by quantitative real-time PCR (qRT-PCR). Additionally, immunohistochemistry (IHC) and western blotting (WB) were applied to evaluate the expression of α-SMA and activation of TGF-ß1-Smad2/3 in lung. RESULTS: USCs highly expressed CD29 and CD90, showing negative expression of hematopoietic stem cell markers (CD45, CD34) and could differentiate into, at least, bone and fat in vitro. In mice challenged with BLM, septal thickening and prominent fibrosis were observed on day 14, with higher HYP content and mRNA levels of TGF-ß1, TNF-α and IL-6 exhibited, compared to untreated mice. USCs could migrate to lung and accumulate there in mouse model after intravenous injection. Transplantation of USCs into BLM-induced mice improved their pulmonary histopathology, decreasing Ashcroft score, Szapiel score, HYP content and mRNA levels of TGF-ß1 and MMP2 of lung, similar to the effects of BMSCs. IHC and WB further revealed that USCs could inhibit activation of the TGF­ß1-Smad2/3 pathway of lung in vivo. CONCLUSIONS: Transplantation of USCs effectively reverses pulmonary fibrotic phenotype in an experimental IPF model, inhibiting the TGF-ß1-Smad2/3 pathway, a key driver of fibrosis. These results suggest the therapeutic application of USCs for IPF, instead of other types of MSCs obtained invasively.

Novel Approach to Enriching Glycosylated RNAs: Specific Capture of GlycoRNAs via Solid-Phase Chemistry.

Ribonuclease (RNA) modifications can alter cellular function and lead to differential immune responses by acting as discriminators between RNAs from different phyla. RNA glycosylation has recently been observed at the cell surface, and its dysregulation in disease may change RNA functions. However, determining which RNA substrates can be glycosylated remains to be explored. Here, we develop a solid-phase chemoenzymatic method (SPCgRNA) for targeting glycosylated RNAs, by which glycosylated RNA substrates can be specifically recognized. We found the differential N-glycosylation of small RNAs in hTERT-HPNE and MIA PaCa-2 cancer cells using SPCgRNA. RNA-Seq showed that the changes in glyco-miRNAs prepared from SPCgRNA were consistent with those of traditional methods. The KEGG signaling pathway analysis revealed that differential miRNA glycosylation can affect tumor cell proliferation and survival. Further studies found that NGI-1 significantly inhibited the proliferation, migration, and circulation of MIA PaCa-2 and promoted cell apoptosis. In addition, ß-1,4-galactosyltransferase 1 (B4GALT1) not only affected the expression level of glycosylated miRNAs hsa-miR-21-5p but also promoted cell apoptosis and inhibited the cell cycle possibly through the p53 signaling pathway, while B4GALT1 and p53 were also affected following the hsa-miR-21-5p increase. These results suggest that B4GALT1 may catalyze miRNAs glycosylation, which further promotes cancer cell progression.

Effect of hydrogen/oxygen therapy for ordinary COVID-19 patients: a propensity-score matched case-control study.

BACKGROUND: Hydrogen/oxygen therapy contribute to ameliorate dyspnea and disease progression in patients with respiratory diseases. Therefore, we hypothesized that hydrogen/oxygen therapy for ordinary coronavirus disease 2019 (COVID-19) patients might reduce the length of hospitalization and increase hospital discharge rates. METHODS: This retrospective, propensity-score matched (PSM) case-control study included 180 patients hospitalized with COVID-19 from 3 centers. After assigned in 1:2 ratios by PSM, 33 patients received hydrogen/oxygen therapy and 55 patients received oxygen therapy included in this study. Primary endpoint was the length of hospitalization. Secondary endpoints were hospital discharge rates and oxygen saturation (SpO2). Vital signs and respiratory symptoms were also observed. RESULTS: Findings confirmed a significantly lower median length of hospitalization (HR = 1.91; 95% CIs, 1.25-2.92; p < 0.05) in the hydrogen/oxygen group (12 days; 95% CI, 9-15) versus the oxygen group (13 days; 95% CI, 11-20). The higher hospital discharge rates were observed in the hydrogen/oxygen group at 21 days (93.9% vs. 74.5%; p < 0.05) and 28 days (97.0% vs. 85.5%; p < 0.05) compared with the oxygen group, except for 14 days (69.7% vs. 56.4%). After 5-day therapy, patients in hydrogen/oxygen group exhibited a higher level of SpO2 compared with that in the oxygen group (98.5%±0.56% vs. 97.8%±1.0%; p < 0.001). In subgroup analysis of patients received hydrogen/oxygen, patients aged < 55 years (p = 0.028) and without comorbidities (p = 0.002) exhibited a shorter hospitalization (median 10 days). CONCLUSION: This study indicated that hydrogen/oxygen might be a useful therapeutic medical gas to enhance SpO2 and shorten length of hospitalization in patients with ordinary COVID-19. Younger patients or those without comorbidities are likely to benefit more from hydrogen/oxygen therapy.

The Patterns of Visual Field Defects in Primary Angle-Closure Glaucoma Compared to High-Tension Glaucoma and Normal-Tension Glaucoma.

INTRODUCTION: The aim of this study was to compare the patterns of visual field (VF) defects in primary angle-closure glaucoma (PACG) to control groups of eyes with high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). METHODS: Forty-eight eyes with PACG were enrolled, and control eyes with HTG and NTG matched for age, sex, and mean deviation of VF defect were selected. VF tests were performed using the 24-2 program of the Humphrey field analyzer. VF defects were classified into six patterns with the Ocular Hypertension Treatment Study classification system and were categorized into three stages (early, moderate, and advanced). Each hemifield was divided into five regions according to the Glaucoma Hemifield Test (GHT). The mean total deviation (TD) of each GHT region was calculated. RESULTS: Compared with HTG and NTG groups, the partial arcuate VF defects were more common in the PACG group. In the PACG group, the nasal GHT region in the inferior hemifield had the worst mean TD (-8.48 ± 8.62 dB), followed by the arcuate 1 (-7.81 ± 7.91 dB), arcuate 2 (-7.46 ± 7.43 dB), paracentral (-7.19 ± 7.98 dB), and central (-5.14 ± 6.24 dB) regions; the mean TD of the central region was significantly better than those for all other regions (all p < 0.05). A similar trend was observed in the superior hemifield in the PACG group but not the VF hemifields of the HTG and NTG groups. CONCLUSION: Patterns of VF defect in PACG patients differ from those with HTG and NTG. This discrepancy might be due to the differences in the pathogenic mechanisms of glaucomatous optic neuropathy.

Investigation of Potential Crucial Genes and Key Pathways in Keratoconus: An Analysis of Gene Expression Omnibus Data.

Keratoconus is one of the most common causes leading to visual impairment in young adult population. The pathogenesis of keratoconus remains poorly understood. The aim of this study was to identify the potential key genes and pathways associated with keratoconus and to further analyze its molecular mechanism. Two RNA-sequencing datasets of keratoconus and paired normal corneal tissues from the Gene Expression Omnibus database were obtained. Differentially expressed genes (DEGs) were identified, and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted. The protein-protein interaction (PPI) network of the DEGs was established, and the hub genes and significant gene modules of PPI were further constructed. Lastly, the GO and KEGG analyses of the hub gene were performed. In total, 548 common DEGs were identified. GO enrichment analysis showed that the DEGs were primarily associated with regulation of cell adhesion, the response to molecule of bacterial origin, lipopolysaccharide and biotic stimulus, collagen-containing extracellular matrix, extracellular matrix, and structure organization. KEGG pathway analysis showed that these DEGs were mainly involved in the TNF signaling pathway, IL-17 signaling pathway, Rheumatoid arthritis, Cytokine-cytokine receptor interaction. The PPI network was constructed with 146 nodes and 276 edges, and 3 significant modules are selected. Finally, top 10 hub genes were identified from the PPI network. The results revealed that extracellular matrix remodeling and immune inflammatory response could be the key links of keratoconus, TNF, IL6, IL1A, IL1B, CCL3, MMP3, MMP9, MMP1, and TGFB1 may be potential crucial genes, and TNF signaling pathway and IL-17 signaling pathway were the potential pathways accounting for pathogenesis and development of keratoconus.

A Novel and Reversible Experimental Primate Ocular Hypertension Model: Blocking Schlemm's Canal.

INTRODUCTION: The purpose of this study was to establish a novel and reversible experimental ocular hypertension primate model by blocking Schlemm's canal. METHODS: A model was induced in adult cynomolgus monkeys (n=4) by blocking Schlemm's canal with an inserted microcatheter (200 µm diameter); it was removed 6 weeks later from one monkey to reverse the elevated intraocular hypertension. All animals were monitored for 11 months; weekly measurements of intraocular pressure and biweekly examinations with spectral domain optical coherence tomography and disc photography were performed. Histopathology of the eye and retinal ganglion cell counts were completed at the end of the study. RESULTS: The intraocular pressure of the blocked eyes was significantly higher than that of the contralateral eyes at 1 month after the blockage (P <0.001); the mean intraocular pressure was similar to the contralateral eye from 1 week to 11 months after the microcatheter was removed in monkey A (P=0.170). The mean intraocular pressure of the blocked eyes of the remaining monkeys was significantly higher than that of the contralateral eyes throughout the follow-up period (P <0.001). The fundus imaging showed decreases in the retinal nerve fibre layer thickness, and localised defects were observed in two blocked eyes. A histological examination demonstrated that the number of retinal ganglion cells in blocked eyes of monkeys A, B, and C was significantly decreased compared with the control. CONCLUSION: Schlemm's canal blockage alone in the monkey model produces sustained elevation of intraocular pressure, which present a novel animal model for studying the pathogenesis of glaucoma.

circ-BPTF serves as a miR-486-5p sponge to regulate CEMIP and promotes hypoxic pulmonary arterial smooth muscle cell proliferation in COPD.

Hypoxia plays a crucial role in pulmonary vascular remodelling at the early stage of chronic obstructive pulmonary disease (COPD). Circle RNA (circRNA) has been identified to play a critical role in multiple diseases. However, the role of circRNAs in pulmonary vascular remodelling in COPD remains unclear. In this study, we aim to investigate the role of circRNAs in pulmonary arterial smooth muscle cell proliferation and pulmonary vascular remodelling in COPD. COPD patients show lower partial pressure of arterial oxygen and pulmonary arterial remodeling as compared with controls. circRNA microarray and real-time PCR analyses show significantly higher level of circ-BPTF and lower miR-486-5p level in the pulmonary arteries of COPD patients as compared with controls. Hypoxia suppresses miR-486-5p expression but promotes expressions of circ-BPTF and cell migration inducing protein (CEMIP) in human pulmonary arterial smooth muscle cells (PASMCs) in vitro. Loss- and gain-of-function experiments show that circ-BPTF promotes PASMC proliferation in vitro. Moreover, luciferase reporter assay results indicate that circ-BPTF regulates PASMC proliferation by acting as an miR-486-5p sponge. CEMIP is identified as a candidate target gene of miR-486-5p by luciferase reporter assay. Overall, our study shows that circ-BPTF serves as a miR-486-5p sponge to regulate CEMIP and promote hypoxic PASMC proliferation in pulmonary vascular remodelling in COPD.

Specific cytokines in the inflammatory cytokine storm of patients with COVID-19-associated acute respiratory distress syndrome and extrapulmonary multiple-organ dysfunction.

BACKGROUND: To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD. METHODS: The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD. RESULTS: The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time. CONCLUSIONS: The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.

Identification of key genes and pathways in scleral extracellular matrix remodeling in glaucoma: Potential therapeutic agents discovered using bioinformatics analysis.

Background: Glaucoma is a leading cause of irreversible blindness. Remodeling of the scleral extracellular matrix (ECM) plays an important role in the development of glaucoma. The aim of this study was to identify the key genes and pathways for the ECM remodeling of sclera in glaucoma by bioinformatics analysis and to explore potential therapeutic agents for glaucoma management. Methods: Genes associated with glaucoma, sclera and ECM remodeling were detected using the text mining tool pubmed2ensembl, and assigned Gene Ontology (GO) biological process terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using the GeneCodis program. A protein-protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape, module analysis was performed using the Molecular Complex Detection (MCODE) plugin, and GO and KEGG analyses of the gene modules were performed using the Database of Annotation, Visualization and Integrated Discovery (DAVID) platform. The genes that clustered in the significant module were selected as core genes, and functions and pathways of the core genes were visualized using ClueGO and CluePedia. Lastly, the drug-gene interaction database was used to explore drug-gene interactions of the core genes to find drug candidates for glaucoma. Results: We identified 125 genes common to "Glaucoma", "Sclera", and "ECM remodeling" by text mining. Gene functional enrichment analysis yielded 30 enriched GO terms and 20 associated KEGG pathways. A PPI network that included 60 nodes with 249 edges was constructed, and three gene modules were obtained using the MCODE. We selected 13 genes that clustered in module 1 as core candidate genes that were associated mainly with ECM degradation and cell proliferation and division. The HIF-1 signaling pathway, FOXO signaling pathway, PI3K-Akt signaling pathway and TGFB signaling pathway were found to be enriched. We found that 11 of the 13 selected genes could be targeted by 26 existing drugs. Conclusions: The results showed that VEGFA, TGFB1, TGFB2, TGFB3, IGF2, IGF1, EGF, FN1, KNG1, TIMP1, SERPINE1, THBS1, and VWF were potential key genes involved to scleral ECM remodeling. Furthermore, 26 drugs were identified as potential therapeutic agents for glaucoma treatment and management.

Primary tracheal papilloma disguised as asthma: A case report.

INTRODUCTION: Tracheal papilloma presenting as asthma is a rare occurrence. CASE STUDY: We report a case of a 32-year-old male patient who presented with features of asthma. Flexible bronchoscopy demonstrated a large growth arising from the lower end of the trachea. Successful treatment using snare loop and argon plasma coagulation (APC) of the polyploidal growth was performed via flexible bronchoscope. RESULTS: The patient had immediate relief of airway obstruction and histopathological examination of the neoplasm demonstrated features of papilloma. CONCLUSION: Primary tracheal papilloma is mimicker of asthma, CT scan should be considered in patients with persistent chronic cough, or stridor. Endoscopic papillectomy is a safe and effective treatment and should be considered as first-line therapy for tracheal papilloma.

[Diagnostic value of computed tomography-guided percutaneous needle biopsy versus radial probe endobronchial ultrasound-guided transbronchial lung biopsy in peripheral pulmonary lesions].

OBJECTIVE: To evaluate the value of computed tomography-guided percutaneous needle biopsy (CT-PNB) and radial probe endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) in the diagnosis of peripheral pulmonary lesions(PPLs). METHODS: The clinical data of 213 patients who were diagnosed as to have PPLs in the First Affiliated Hospital of Soochow University between December 1, 2012 and October 1, 2014 were studied retrospectively. The patients were divided into CT-PNB group and EBUS-TBLB group, according to biopsy methods. The diagnostic yield, complications and influencing factors of both groups were evaluated. RESULTS: The diagnostic yield (87.2%, 102/117) and complication rate (18.8%, 22/117) of the CT-PNB group were higher than those of the EBUS-TBLB group(61.5%, 59/96 and 18.8%, 22/117, respectively), the differences being statistically significant (χ(2)=18.906, P=0.000 and χ(2)=10.542, P=0.001, respectively). Analysis of the influencing factors showed that there were statistically significant correlations between pneumothorax and the lesion diameter(χ(2)=5.785, P=0.016) and location(χ(2)=7.559, P=0.006) in the CT-PNB group. The diagnostic yield was correlated with lesion diameter(χ(2)=7.995, P=0.004) and location(χ(2)=4.608, P=0.027) in the EBUS-TBLB group. There was no complicated pneumothorax if the lesions were attached to the chest wall in the CT-PNB group. CONCLUSIONS: The diagnostic yield of CT-PNB in PPLs was better than that of EBUS-TBLB. Although CT-PNB had a higher complication rates, most complications were mild.

A bronchoscopic navigation method based on neural radiation fields.

PURPOSE: We introduce a novel approach for bronchoscopic navigation that leverages neural radiance fields (NeRF) to passively locate the endoscope solely from bronchoscopic images. This approach aims to overcome the limitations and challenges of current bronchoscopic navigation tools that rely on external infrastructures or require active adjustment of the bronchoscope. METHODS: To address the challenges, we leverage NeRF for bronchoscopic navigation, enabling passive endoscope localization from bronchoscopic images. We develop a two-stage pipeline: offline training using preoperative data and online passive pose estimation during surgery. To enhance performance, we employ Anderson acceleration and incorporate semantic appearance transfer to deal with the sim-to-real gap between training and inference stages. RESULTS: We assessed the viability of our approach by conducting tests on virtual bronchscopic images and a physical phantom against the SLAM-based methods. The average rotation error in our virtual dataset is about 3.18 ∘ and the translation error is around 4.95 mm. On the physical phantom test, the average rotation and translation error are approximately 5.14 ∘ and 13.12 mm. CONCLUSION: Our NeRF-based bronchoscopic navigation method eliminates reliance on external infrastructures and active adjustments, offering promising advancements in bronchoscopic navigation. Experimental validation on simulation and real-world phantom models demonstrates its efficacy in addressing challenges like low texture and challenging lighting conditions.

Study on the rationality of small diameter metallic airway stent in treatment of tracheal stenosis in injured rabbits.

BACKGROUND: To observe the occurrence of related complications after self-expandable metallic (SEM) airway stents implantation with different diameters at different time points, and to provide theoretical basis for the optimal chioce of existing airway stents in clinical practice. METHODS: Healthy New Zealand white rabbits were used to establish benign tracheal stenosis models after chest CT examination. Forty-fivemodel rabbits with more than 50% of airway stenosis were divided into two groups. Small-diameter SEM stents (The ratio of stent diameter to airway diameter is nearly 1.0) were implanted in Group A in 21 rabbits, and large-diameter tracheal stents (The ratio of stent diameter to airway diameter is more than 1.2) were implanted in Group B in 24 rabbits. Stent-related complications were observed after stent implantation in 2nd,4th,8th, and 12th week by bronchoscopygross anatomy, pathological and the expressions of IL-1RA, IL-8 and MMP9 in involved tracheal. RESULTS: The incidence rate of tracheomalacia of stent was significantly higher in group B (24/24 100%) than that in group A (1 /21,4.8%) (P < 0.05). The incidence rate of scar contracture at both ends of stent was significantly higher than in group B (11 / 24,45.8%) that in group A (2 /21, 9.5%) (P < 0.05). The pathological results of both A and B showed that the columnar epithelium of bronchial mucosa began to damage and detach, inflammatory cells infiltrated after 2nd and 4th week of stenting, The epithelium was repaired, the lamina propria glands almost disappeared, collagen fiber proliferation was obvious, and scars were formed after 8th and 12th week of stenting. ELISA results revealed that the expressions of IL-1RA, IL-8, and MMP9 were increased in the stent group than in model rabbit with benign tracheal stenosis. IL-1RA and MMP9 increased at different periods in group B, but the expression of IL-1RA and MMP9 showed a tread of increasing in the early stage and then decreasing in group A. CONCLUSION: Metal stents can cause different degrees of stent-related complications in rabbits with benign tracheal stenosis. The incidence of stent-induced tracheomalacia and scar contracture were higher in Group B than that in Group A. IL-1RA, IL-8 and MMP9 may be involved in the development of complications after stentimplantation and peak value of group B movered backward. ing.

SAMHD1 dysfunction induces IL-34 expression via NF-κB p65 in neuronal SH-SY5Y cells.

Dysfunctional mutations in SAMHD1 cause Aicardi-Goutières Syndrome, an autoinflammatory encephalopathy with elevated interferon-α levels in the cerebrospinal fluid. Whether loss of function mutations in SAMHD1 trigger the expression of other cytokines apart from type I interferons in Aicardi-Goutières Syndrome is largely unclear. This study aimed to explore whether SAMHD1 dysfunction regulated the expression of IL-34, a key cytokine controlling the development and maintenance of microglia, in SH-SY5Y neural cells. We found that downregulation of SAMHD1 in SH-SY5Y cells resulted in the upregulation of IL-34 expression. The protein and mRNA levels of NF-κB p65, the transactivating subunit of a transcription factor NF-κB, were also upregulated in SAMHD1-knockdown SH-SY5Y cells. It was further found SAMHD1 knockdown in SH-SY5Y cells induced an upregulation of IL-34 expression through the canonical NF-κB-dependent pathway in which NF-κB p65, IKKα/ß and the NF-κB inhibitor IκBα were phosphorylated. Moreover, knockdown of SAMHD1 in SH-SY5Y cells led to the translocation of NF-κB p65 into the nucleus and promoted NF-κB transcriptional activity. In conclusion, we found SAMHD1 dysfunction induced IL-34 expression via NF-κB p65 in neuronal SH-SY5Y cells. This finding could lay the foundation for exploring the role of IL-34-targeting microglia in the pathogenesis of Aicardi-Goutières Syndrome.

SIRPG promotes lung squamous cell carcinoma pathogenesis via M1 macrophages: a multi-omics study integrating data and Mendelian randomization.

Background: Squamous cell carcinoma of the lung (LUSC) is a severe and highly lethal malignant tumor of the respiratory system, and its molecular mechanisms at the molecular level remain unc\lear. Methods: We acquired RNA-seq data from 8 surgical samples obtained from early-stage LUSC and adjacent non-cancerous tissues from 3 different centers. Utilizing Deseq2, we identified 1088 differentially expressed genes with |LogFC| > 1 and a p-value < 0.05 threshold. Furthermore, through MR analysis of Exposure Data for 26,153 Genes and 63,053 LUSC Patients, incorporating 7,838,805 SNPs as endpoints, we identified 213 genes as potential exposure factors. Results: After intersecting the results, we identified 5 differentially expressed genes, including GYPE, PODXL2, RNF182, SIRPG, and WNT7A. PODXL2 (OR 95% CI, 1.169 (1.040 to 1.313)) was identified as an exposed risk factor, with p-values less than 0.01 under the inverse variance weighted model. GO and KEGG analyses revealed enhanced ubiquitin-protein transferase activity and activation of pathways such as the mTOR signaling pathway and Wnt signaling pathway. Immune infiltration analysis showed downregulation of Plasma cells, T cells regulatory (Tregs), and Dendritic cells activated by the identified gene set, while an enhancement was observed in Macrophages M1. Furthermore, we externally validated the expression levels of these five genes using RNA-seq data from TCGA database and 11 GEO datasets of LUSC, and the results showed SIRPG could induce LUSC. Conclusion: SIRPG emerged as a noteworthy exposure risk factor for LUSC. Immune infiltration analysis highlighted Macrophages M1 and mTOR signaling pathway play an important role in LUSC.

Genetically Proxied Therapeutic Effect of Metformin Use, Blood Pressure, and Hypertension's Risk: a Drug Target-Based Mendelian Randomization Study.

In this work, we aim to evaluate the association of the genetically proxied effect of metformin on blood pressure (BP) and hypertension through a drug target-based Mendelian randomization (MR) analysis. Thirty-two instrumental variables for five metformin targets (i.e., AMP-activated protein kinase (AMPK), growth differentiation factor 15 (GDF15), mitochondrial glycerol 3 (MG3), mitochondrial complex I (MCI), and glucagon (GCG)) were introduced to the MR analysis on the datasets of hypertension, systolic and diastolic blood pressure (SBP and DBP). The MR analyses demonstrated that the MCI- and MG3-specific metformin's use would significantly reduce SBP, DBP, and hypertension risk. The meta-analyses showed that the genetically proxied metformin's use equivalent to a 6.75 mmol/mol reduction on HbA1c could decrease both the SBP (beta = - 1.05, P < 0.001) and DBP (beta = - 0.51, P = 0.096). Furthermore, metformin's use was also implied to reduce the hypertension risk. The MG3- and MCI-dependent metformin's effect may play key roles in the anti-hypertension function.