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The funding details have been incorporated upon author's request in the funding section of this article titled "B2M is a Biomarker Associated With Immune Infiltration In High Altitude Pulmonary Edema ," 2024, 27(1), 168-185 [1]. Details of the error and a correction are provided here. Original: This work was supported by grants from the Chongqing Natural Science Gene General Project (No. YWRYPYG). Corrected: This work was supported by General Project of Chongqing Natural Science Foundation cstc2020jcyj-msxmX0227. We regret the error and apologize to the readers. The original article can be found online at www.eurekaselect.com/article/131669.
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BACKGROUND: Aberrant keratinocytes differentiation has been demonstrated to be associated with a number of skin diseases. The roles of lncRNAs in keratinocytes differentiation remain to be largely unknown. OBJECTIVE: Here we aim to investigate the role of lnc-DC in regulating epidermal keratinocytes differentiation. METHODS: Expression of lnc-DC in the skin was queried in AnnoLnc and verified by FISH. The lncRNA expression profiles during keratinocytes differentiation were reanalyzed and verified by qPCR and FISH. Gene knock-down and over-expression were used to explore the role of lnc-DC in keratinocytes differentiation. The downstream target of lnc-DC was screened by whole transcriptome sequencing. CUT&RUN assay and siRNAs transfection was used to reveal the regulatory effect of GRHL3 on lnc-DC. The mechanism of lnc-DC regulating ZNF750 was revealed by RIP assay and RNA stability assay. RESULTS: Lnc-DC was biasedly expressed in skin and up-regulated during epidermal keratinocytes differentiation. Knockdown lnc-DC repressed epidermal keratinocytes differentiation while over-express lnc-DC showed the opposite effect. GRHL3, a well-known transcription factor regulating keratinocytes differentiation, could bind to the promoter of lnc-DC and regulate its expression. By whole transcriptome sequencing, we identified that ZNF750 was a downstream target of lnc-DC during keratinocytes differentiation. Mechanistically, lnc-DC interacted with RNA binding protein IGF2BP2 to stabilize ZNF750 mRNA and up- regulated its downstream targets TINCR and KLF4. CONCLUSION: Our study revealed the novel role of GRHL3/lnc-DC/ZNF750 axis in regulating epidermal keratinocytes differentiation, which may provide new therapeutic targets of aberrant keratinocytes differentiation related skin diseases.
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RNA, Long Noncoding , Skin Diseases , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Transcription Factors/metabolism , Keratinocytes/metabolism , Skin/metabolism , Skin Diseases/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , RNA-Binding Proteins/metabolism , Tumor Suppressor Proteins/metabolismABSTRACT
It is of great significance to accurately and sensitively detect oral cancer-related biomarkers (ORAOV 1) for the early diagnosis of oral cancer. Present here is a novel electrochemical biosensor based on Cu2+-doped zeolitic imidazolate frameworks and gold nanoparticle (AuNPs@ZIF-8/Cu) nanocomposites and a one-step strand displacement reaction for label-free, simple and sensitive detection of ORAOV 1 in saliva. It is worth noting that AuNPs@ZIF-8/Cu nanocomposites show large electrochemically effective surface area, good electrical conductivity and electrocatalytic activity due to the synergistic effect of metal nanoparticles (MNPs) and ZIF-8. Consequently, the newly developed electrochemical sensor displays a wide linear range of 0.1-104 pM and a low limit of detection (LOD) of 63 fM. Meanwhile, the electrochemical biosensor can distinguish single base mismatch. The relative standard deviation (RSD) of intra-assays and inter-assays is 1.46% and 1.76%, respectively, and the peak current values decline by 9.20% with a RSD value of 1.35% after being stored at 4 °C for 7 days, suggesting that the newly designed electrochemical sensor exhibits good selectivity, reproducibility and stability to detect ORAOV 1. More importantly, this novel electrochemical sensor is found to be applicable for detecting ORAOV 1 in human saliva samples with a satisfactory result. The RSD values range from 1.15% to 1.77%, and the recoveries range from 95.46% to 112.98%.
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Metal Nanoparticles , Mouth Neoplasms , Nanocomposites , Zeolites , Humans , Biomarkers, Tumor , Gold , Reproducibility of Results , Mouth Neoplasms/diagnosisABSTRACT
Aqueous zinc-ion batteries (AZIBs) have demonstrated great potential for large-scale energy storage. However, their practical applications have been restricted by fast Zn dendrite growth and severe side reactions at the Zn/electrolyte interface. Herein, sodium gluconate is incorporated into a mild acidic electrolyte as a multifunctional additive to stabilize the Zn anode. Experiments and theoretical calculations reveal that the SG additive can induce planar growth of Zn along its (002) direction, thereby inhibiting Zn dendrite growth. This dendrite inhibition effect is attributed to the preferential adsorption of Zn2+ on the Zn (002) plane, while the Zn (100) and (101) planes are shielded by gluconate ions. Consequently, Zn||Zn symmetric cells with the electrolyte additive exhibit significantly prolonged cycle lives of 2000 h at 1 mA cm-2, 1 mA h cm-2 and 900 h at 5 mA cm-2, 2.5 mA h cm-2. Futhermore, the Zn||NH4V4O10 full cell retains 95% of its initial capacity after 2000 cycles at a current density of 5 A g-1 with an average CE of nearly 100%. This work offers a cost-effective strategy to enhance the electrochemical performance of AZIBs.
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INTRODUCTION: This study was to investigate the diagnostic value of percutaneous closed pleural brushing (CPBR) followed by cell block technique for malignant pleural effusion (MPE) and the predictive efficacy of pleural fluid carcinoembryonic antigen (CEA) for epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma patients with MPE. METHODS: All patients underwent closed pleural biopsy (CPB) and CPBR followed by cell block examination. MPE-positive diagnostic rates between the two methods were compared. Univariate and multivariate analyses were performed to determine factors influencing the EGFR mutations. Receiver operating characteristic (ROC) curve was used to analyze the predictive efficacy of pleural fluid CEA for EGFR mutations. RESULTS: The cumulative positive diagnostic rates for MPE after single and twice CPBR followed by cell block examination were 80.5% and 89.0%, higher than CPB (45.7%, 54.3%) (P < 0.001). Univariate analysis showed that EGFR mutation was associated with pleural fluid and serum CEA (P < 0.05). Multivariate analysis showed that pleural fluid CEA was an independent risk factor for predicting EGFR mutation (P < 0.001). The area under the curve (AUC) of pleural fluid CEA for EGFR mutation prediction was 0.774, higher than serum CEA (P = 0.043), but no difference with the combined test (P > 0.05). CONCLUSION: Compared with CPB, CPBR followed by the cell block technique can significantly increase the positive diagnostic rate of suspected MPE. CEA testing of pleural fluid after CPBR has a high predictive efficacy for EGFR mutation in lung adenocarcinoma patients with MPE, implying pleural fluid extracted for cell block after CPBR may be an ideal specimen for genetic testing.
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Adenocarcinoma of Lung , Lung Neoplasms , Pleural Effusion, Malignant , Pleural Effusion , Humans , Pleural Effusion, Malignant/diagnosis , Pleural Effusion, Malignant/genetics , Pleural Effusion, Malignant/metabolism , Carcinoembryonic Antigen/metabolism , Biomarkers, Tumor/metabolism , Adenocarcinoma of Lung/diagnosis , Adenocarcinoma of Lung/genetics , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , ErbB Receptors/genetics , Pleural Effusion/diagnosisABSTRACT
BACKGROUND: High altitude pulmonary edema (HAPE) is a serious mountain sickness with certain mortality. Its early diagnosis is very important. However, the mechanism of its onset and progression is still controversial. AIM: This study aimed to analyze the HAPE occurrence and development mechanism and search for prospective biomarkers in peripheral blood. METHODS: The difference genes (DEGs) of the Control group and the HAPE group were enriched by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and then GSEA analysis was performed. After identifying the immune-related hub genes, QPCR was used to verify and analyze the hub gene function and diagnostic value with single-gene GSEA and ROC curves, and the drugs that acted on the hub gene was found in the CTD database. Immune infiltration and its association with the hub genes were analyzed using CIBERSORT. Finally, WGCNA was employed to investigate immune invasion cells' significantly related gene modules, following enrichment analysis of their GO and KEGG. RESULTS: The dataset enrichment analysis, immune invasion analysis and WGCNA analysis showed that the occurrence and early progression of HAPE were unrelated to inflammation. The hub genes associated with immunity obtained with MCODE algorithm of Cytoscape were JAK2 and B2M.. RT-qPCR and ROC curves confirmed that the hub gene B2M was a specific biomarker of HAPE and had diagnostic value, and single-gene GSEA analysis confirmed that it participated in MHC I molecule-mediated antigen presentation ability decreased, resulting in reduced immunity. CONCLUSION: Occurrence and early progression of high altitude pulmonary edema may not be related to inflammation. B2M may be a new clinical potential biomarker for HAPE for early diagnosis and therapeutic evaluation as well as therapeutic targets, and its decrease may be related to reduced immunity due to reduced ability of MCH I to participate in antigen submission.
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Altitude Sickness , Hypertension, Pulmonary , Pulmonary Edema , Humans , Altitude Sickness/diagnosis , Altitude Sickness/genetics , Altitude , Biomarkers , Inflammation , Computational BiologyABSTRACT
Most thrombopoietin receptor (MPL) mutations result in abnormal megakaryocyte expansion in the spleen or bone marrow (BM), leading to progressive fibrosis. It has been reported that p21 (Rac Family Small GTPase 1 [RAC1])-activated kinase 1 (PAK1) participates in the proliferation and differentiation of megakaryoblasts. PAK1 phosphorylation increased in patients with myeloproliferative neoplasms (MPNs) and murine MPN cells with the Mplw515l mutant gene in this study; however, the function of overactivated PAK1 in MPN cells remains unclear. We found that inhibition of PAK1 caused significant changes in the biological behaviors of MPLW515L mutant cells in vitro, including arrested growth or reduced clonality and increased polyploid DNA and cell apoptosis due to upregulated cleaved caspase 3. In vivo, PAK1 inhibitor treatment caused a slow elevation of leukocytosis and hematocrit (HCT) and a reduction in hepatosplenomegaly in 6133/MPLW515L-transplanted mice, along with reduced tumor cell infiltration and prolonged survival. Further, deletion of PAK1 sustained a relatively normal HCT and platelet count at the beginning of the disease but did not completely alleviate the splenomegaly of MPLW515L mutant mice. Notably, PAK1 knockout attenuated the destruction of splenic structure, and reduced the megakaryocyte burden within the BM. These results suggest that inhibition of PAK1 may be a useful method for treating MPLW515L mutant MPN by intervening megakaryocytes.
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Myeloproliferative Disorders , Neoplasms , Humans , Mice , Animals , Megakaryocytes/pathology , Cell Proliferation , Neoplasms/pathology , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/pathology , Cell Differentiation , p21-Activated Kinases/genetics , p21-Activated Kinases/pharmacologyABSTRACT
BACKGROUND: The aim of this study was to evaluate the safety, efficacy, and oncologic outcomes of neoadjuvant immunotherapy combined with chemotherapy (NICT) group and surgery alone group in the treatment of patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: A series of 232 consecutive patients who underwent surgery with or without NICT from June 2019 to August 2022 were evaluated. We performed propensity score matching between the NICT and surgery alone groups on the basis of estimated propensity scores for each patient. RESULTS: After propensity score matching, data of 137 patients with clinical stages II-IV ESCC, including 85 receiving surgery alone and 52 receiving NICT, were analyzed. Compared with the surgery alone group (301.7 ± 94.4 min), the operation time was significantly longer in the NICT group (333.4 ± 79.7 min). However, there was no significant difference between the two groups in the postoperative complications, intraoperative blood loss, thoracic fluid volume, chest tube duration, lengths of intensive care unit stay and postoperative hospitalization. Additionally, 90-day mortality rate and 30-day readmission were similar in both groups. CONCLUSIONS: Overall, NICT followed by esophagectomy appears to be safe and feasible for locally advanced ESCC. However, further multicenter prospective clinical trials are needed to validate our results.
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Carcinoma, Squamous Cell , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Esophageal Neoplasms/surgery , Propensity Score , Carcinoma, Squamous Cell/surgery , Neoadjuvant Therapy/methods , Prospective Studies , Treatment Outcome , Immunotherapy , Esophagectomy , Retrospective StudiesABSTRACT
Background: Total pharyngolaryngoesophagectomy (TPLE) is considered as a curative treatment for hypopharynx cancer and cervical esophageal carcinomas (HPCECs). Traditional pharyngo-gastric anastomosis is usually performed manually, and postoperative complications are common. The aim of this study was to introduce a new technique for mechanical anastomosis and to evaluate perioperative outcomes and prognosis. Methods: From May 1995 to Nov 2021, a series of 75 consecutive patients who received TPLE for a pathological diagnosis of HPCECs at Sun Yat-sen Memorial Hospital were evaluated. Mechanical anastomosis was performed in 28 cases and manual anastomosis was performed in 47 cases. The data from these patients were retrospectively analyzed. Results: The mean age was 57.6 years, and 20% of the patients were female. The rate of anastomotic fistula and wound infection in the mechanical group were significantly lower than that in the manual group. The operation time, intraoperative blood loss and postoperative hospital stays were significantly higher in the manual group than that in the mechanical group. The R0 resection rate and the tumor characteristics were not significantly different between groups. There was no significant difference in overall survival and disease-free survival between the two groups. Conclusion: The mechanical anastomosis technology adopted by this study was shown to be a safer and more effective procedure with similar survival comparable to that of manual anastomosis for the HPCECs patients.
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Background: Lipid metabolism reprogramming played an important role in cancer occurrence, development, and immune regulation. The aim of this study was to identify and validate lipid metabolism-related genes (LMRGs) associated with the phenotype, prognosis, and immunological characteristics of lung squamous cell carcinoma (LUSC). Methods: In the TCGA cohort, bioinformatics and survival analysis were used to identify lipid metabolism-related differentially expressed genes (DEGs) associated with the prognosis of LUSC. PTGIS/HRASLS knockdown and overexpression effects on the LUSC phenotype were analyzed in vitro experiments. Based on the expression distribution of PTGIS/HRASLS, LUSC patients were divided into two clusters by consensus clustering. Clinical information, prognosis, immune infiltration, expression of immune checkpoints, and tumor mutation burden (TMB) level were compared between the TCGA and GSE4573 cohorts. The genes related to clustering and tumor immunity were screened by weighted gene coexpression network analysis (WGCNA), and the target module genes were analyzed by functional enrichment analysis, protein-protein interaction (PPI) analysis, and immune correlation analysis. Results: 191 lipid metabolism-related DEGs were identified, of which 5 genes were independent prognostic genes of LUSC. PTGIS/HRASLS were most closely related to LUSC prognosis and immunity. RT-qPCR, western blot (WB) analysis, and immunohistochemistry (IHC) showed that the expression of PTGIS was low in LUSC, while HRASLS was high. Functionally, PTGIS promoted LUSC proliferation, migration, and invasion, while HRASLS inhibited LUSC proliferation, migration, and invasion. The two clusters' expression and distribution of PTGIS/HRASLS had the opposite trend. Cluster 1 was associated with lower pathological staging (pT, pN, and pTNM stages), better prognosis, stronger immune infiltration, higher expression of immune checkpoints, and higher TMB level than cluster 2. WGCNA found that 28 genes including CD4 and IL10RA were related to the expression of PTGIS/HRASLS and tumor immune infiltration. PTGIS/HRASLS in the GSE4573 cohort had the same effect on LUSC prognosis and tumor immunity as the TCGA cohort. Conclusions: PTGIS and HRASLS can be used as new therapeutic targets for LUSC as well as biomarkers for prognosis and tumor immunity, which has positive significance for guiding the immunotherapy of LUSC.
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Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Cytochrome P-450 Enzyme System , Lung Neoplasms , Phospholipases A , Humans , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , Cytochrome P-450 Enzyme System/genetics , Gene Expression Regulation, Neoplastic , Lipid Metabolism/genetics , Lung , Lung Neoplasms/genetics , Phenotype , Phospholipases A/geneticsABSTRACT
OBJECTIVE: To investigate whether serum uric acid (SUA) level is associated with all-cause and cardiovascular disease (CVD) mortality among individuals with diabetes. RESEARCH DESIGN AND METHODS: In this prospective cohort study, we included patients with diabetes from the U.S. National Health and Nutritional Examination Survey (NHANES) 1999-2018. Mortality and underlying causes of death were ascertained by linkage to national death records through 31 December 2019. Weighted Cox proportional hazards regression models were used to evaluate hazard ratios (HRs) and 95% CIs for all-cause and CVD mortality. We also performed a meta-analysis of available cohort studies to combine the association between SUA level and mortality in diabetes. RESULTS: Among the 7,101 patients with diabetes from NHANES 1999-2018, the weighted mean of SUA level was 5.7 mg/dL. During 57,926 person-years of follow-up, 1,900 deaths (n = 674 deaths from CVD) occurred. In the fully adjusted model, when compared with patients with diabetes in the lowest SUA quintile, those in the highest SUA quintile had the HRs (95% CIs) of 1.28 (1.03, 1.58) for all-cause mortality and 1.41 (1.03, 1.94) for CVD mortality. We included 13 cohort studies in the meta-analysis and found that the pooled HRs (95% CIs) were 1.08 (1.05, 1.11) for all-cause mortality and 1.05 (1.03, 1.06) for CVD mortality per 1 mg/dL increment of SUA level in patients with diabetes. CONCLUSIONS: This study indicated that higher SUA levels were associated with increased risks of all-cause and CVD mortality in diabetes. Interventional studies are needed to elucidate the health effect of treatments to lower SUA levels.
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Cardiovascular Diseases , Diabetes Mellitus , Humans , Uric Acid , Prospective Studies , Nutrition Surveys , Risk FactorsABSTRACT
Necroptosis is a new programmed formation of necrotizing cell death, which plays important role in tumor biological regulation, including tumorigenesis and immunity. In this study, we aimed to establish and validate a prediction model based on necroptosis-related genes (NRGs) for lung adenocarcinoma (LUAD) prognosis and tumor immunity. The training set consisted of samples from The Cancer Genome Atlas (TCGA) dataset (n = 334), and the validation sets consisted of samples from the Gene Expression Omnibus (GEO) (n = 439) and clinical (n = 20) datasets. Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that 28 necroptosis-related differentially expressed genes (DEGs) were enriched in cell death and immune regulation. RT-qPCR and western blot results showed the low expression of necroptosis markers in LUAD cells. A prognostic gene signature based on 6 NRGs (PYGB, IL1A, IFNAR2, BIRC3, H2AFY2, and H2AFX) was constructed and the risk score was calculated. Multivariate Cox regression analysis showed that the risk score was an independent risk factor [hazard ratio (HR) = 1.220, 95% confidence interval (CI): 1.154-1.290, P<0.001]. In the TCGA cohort, a high-risk score was associated with poor prognosis, weak immune infiltration, and low expression at immune checkpoints, which was validated in the GEO and clinical cohorts. Our findings showed that the patients in the low-risk group had a better progression-free survival (PFS) [not reached vs. 8.5 months, HR = 0.18, 95% CI: 0.04-0.72, P<0.001] than those in the high-risk score group. Immunotherapy tolerance was found to be correlated with the high-risk score, and the risk score combined with PD-L1 (AUC = 0.808, 95% CI: 0.613-1.000) could better predict the immunotherapy response of LUAD. A nomogram was shown to have a strong ability to predict the individual survival rate of patients with LUAD in the TCGA and GSE68465 cohorts. We constructed and validated a potential prognostic signature consisting of 6 NRGs to predict the prognosis and tumor immunity of LUAD, which may be helpful to guide the individualized immunotherapy of LUAD.
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Background: Hepatocellular carcinoma is one kind of clinical common malignant tumor with a poor prognosis, and its pathogenesis remains to be clarified urgently. This study was performed to elucidate key genes involving HCC by bioinformatics analysis and experimental evaluation. Methods: We identified common differentially expressed genes (DEGs) based on gene expression profile data of GSE60502 and GSE84402 from the Gene Expression Omnibus (GEO) database. Gene Ontology enrichment analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, REACTOME pathway enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were used to analyze functions of these genes. The protein-protein interaction (PPI) network was constructed using Cytoscape software based on the STRING database, and Molecular Complex Detection (MCODE) was used to pick out two significant modules. Hub genes, screened by the CytoHubba plug-in, were validated by Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas (HPA) database. Then, the correlation between hub genes expression and immune cell infiltration was evaluated by Tumor IMmune Estimation Resource (TIMER) database, and the prognostic values were analyzed by Kaplan-Meier plotter. Finally, biological experiments were performed to illustrate the functions of RRM2. Results: Through integrated bioinformatics analysis, we found that the upregulated DEGs were related to cell cycle and cell division, while the downregulated DEGs were associated with various metabolic processes and complement cascade. RRM2, MAD2L1, MELK, NCAPG, and ASPM, selected as hub genes, were all correlated with poor overall prognosis in HCC. The novel RRM2 inhibitor osalmid had anti-tumor activity, including inhibiting proliferation and migration, promoting cell apoptosis, blocking cell cycle, and inducing DNA damage of HCC cells. Conclusion: The critical pathways and hub genes in HCC progression were screened out, and targeting RRM2 contributed to developing new therapeutic strategies for HCC.
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Chronic non-healing wounds fail to progress beyond the inflammatory phase, characterized by a disorder of inflammation resolution. PD-1/PD-L1, a major co-inhibitory checkpoint signaling, plays critical roles in tumor immune surveillance and the occurrence of inflammatory or autoimmune diseases, but its roles in wound healing remains unclear. Here, we described a novel function of PD-L1 in fibroblast-like cells as a positive regulator of wound healing. PD-L1 dynamically expressed on the fibroblast-like cells in the granulation tissue during wound healing to form a wound immunosuppressive microenvironment, modulate macrophages polarization from M1-type to M2-type, and initiates resolution of inflammation, finally accelerate wound healing. Loss of PD-L1 delayed wound healing, especially in mice with LPS-induced severe inflammation. Furthermore, the mainly regulatory mechanism is that combination of FGF-2 and TGF-ß1 promotes PD-L1 translation in fibroblasts through enhancing the eIF4E availability regulated by both PI3K-AKT-mTOR-4EBP1 and p38-ERK-MNK signaling pathways. Our results reveal the positive role of PD-L1 in wound healing, and provide a new strategy for the treatment of chronic wounds.
Subject(s)
B7-H1 Antigen , Phosphatidylinositol 3-Kinases , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Fibroblasts/metabolism , Inflammation/metabolism , Mice , Phosphatidylinositol 3-Kinases/metabolism , Wound Healing/geneticsABSTRACT
Acute megakaryoblastic leukaemia (AMKL) is characterized by expansion of megakaryoblasts, which are hyper-proliferative cells that fail to undergo differentiation. Insight to the cell-cycle regulation revealed important events in early or late megakaryocytes (MKs) maturation; the cyclin-dependent kinases 4 and 6 (CDK4/6) have been reported to participate in the development of progenitor megakaryocytes, mainly by promoting cell cycle progression and DNA polyploidization. However, it remains unclear whether the continuous proliferation, but not differentiation, of megakaryoblasts is related to an aberrant regulation of CDK4/6 in AMKL. Here, we found that CDK4/6 were up regulated in patients with AMKL, and persistently maintained at a high level during the differentiation of abnormal megakaryocytes in vitro, according to a database and western blot. Additionally, AMKL cells were exceptionally reliant on the cell cycle regulators CDK4 or 6, as blocking their activity using an inhibitor or short hairpin RNA (shRNA) significantly reduced the proliferation of 6133/MPL megakaryocytes, reduced DNA polyploidy, induced apoptosis, decreased the level of phosphorylated retinoblastoma protein (p-Rb), and activation of caspase 3. Additionally, CDK4/6 inhibitors and shRNA reduced the numbers of leukemia cells in the liver and bone marrow (BM), alleviated hepatosplenomegaly, and prolonged the survival of AMKL-transplanted mice. These results suggested that blocking the activity of CDK4/6 may represent an effective approach to control megakaryoblasts in AMKL.
Subject(s)
Leukemia, Megakaryoblastic, Acute , Animals , Cyclins , DNA , Leukemia, Megakaryoblastic, Acute/drug therapy , Leukemia, Megakaryoblastic, Acute/genetics , Megakaryocyte Progenitor Cells , Mice , RNA, Small InterferingABSTRACT
Purpose: This study aimed to investigate the relationship of partial pressure of carbon dioxide (PaCO2) with BODE and GOLD in stable COPD subjects and to explore the predictive value of PaCO2 for severe COPD (BODE index score ≥5 or GOLD index score ≥3). Patients and Methods. In total, 80 participants with COPD and free from other conditions affecting PaCO2 were recruited. Arterial blood gases, BODE, GOLD, SGRQ, lung function, and other data were collected. The BODE index was calculated, and patients were divided into two groups according to the BODE index and PaCO2 median, respectively. We used Pearson's correlation test and the receiver operating characteristic curves to evaluate the utility of PaCO2. Besides, the univariate and multivariate logistic regression analyses were conducted to verify whether PaCO2 was an independent factor associated with BODE grades. Results: COPD subjects with BODE ≥5 and GOLD ≥3 had significantly higher levels of PaCO2 (p = 0.004, p = 0.001, respectively). In the high PaCO2 group, patients underwent poorer outcomes than the low PaCO2 group. PaCO2 was negatively correlated with forced expiratory volume in 1 second in percent of the predicted value (FEV1%) (r = -0.612, p < 0.001). The performance of PaCO2 levels in predicting BODE ≥5 and GOLD ≥3 was 0.748 and 0.755, respectively. The logistic regression analyses proved that PaCO2 was associated with BODE ≥5 in COPD patients (odds ratio = 1.160, 95% CI: 1.025-1.313, p = 0.019). Conclusions: A higher level of PaCO2 was associated with a higher index for BODE or GOLD in COPD and had the predictive value for severe COPD.
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Carbon Dioxide , Pulmonary Disease, Chronic Obstructive , Forced Expiratory Volume , Humans , Partial Pressure , Pulmonary Disease, Chronic Obstructive/diagnosis , Severity of Illness IndexABSTRACT
OBJECTIVE: To assess the relationship between chronic obstructive pulmonary disease (COPD) severity and bone mineral density (BMD) in the whole body and different body areas. METHODS: This retrospective, cross-sectional study included patients with COPD. Demographic and lung function data, COPD severity scales, BMD, and T scores were collected. Patients were grouped by high (≥-1) and low (<-1) T scores, and stratified by body mass index, airway obstruction, dyspnoea, and exercise capacity (BODE) index. The relationship between whole-body BMD and BODE was evaluated by Kendall's tau-b correlation coefficient. Risk factors associated with COPD severity were identified by univariate analyses. BMD as an independent predictor of severe COPD (BODE ≥5) was verified by multivariate logistic regression. BMD values in different body areas for predicting severe COPD were assessed by receiver operating characteristic curves. RESULTS: Of 88 patients with COPD, lung-function indicators and COPD severity were significantly different between those with high and low T scores. Whole-body BMD was inversely related to COPD severity scales, including BODE. Multivariate logistic regression revealed that BMD was independently associated with COPD severity. The area under the curve for pelvic BMD in predicting severe COPD was 0.728. CONCLUSION: BMD may be a novel marker in predicting COPD severity, and pelvic BMD may have the strongest relative predictive power.
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Bone Density , Pulmonary Disease, Chronic Obstructive , Body Mass Index , Cross-Sectional Studies , Dyspnea , Humans , Pulmonary Disease, Chronic Obstructive/complications , Retrospective Studies , Severity of Illness IndexABSTRACT
Background: The peroxisome proliferator-activated receptor γ (PPARγ) promotes autophagy and regulates the inflammatory response. However, the effects of the PPARγ on inflammation in acute respiratory distress syndrome (ARDS) are unclear. This study sought to explore the mechanism by which the downregulation of microRNA-129-5p (miR-129-5p) attenuates the inflammatory response in ARDS patients by regulating PPARγ-mediated autophagy. Methods: Lipopolysaccharide (LPS) was used to establish an acute lung injury (ALI) mice model to simulate ARDS. GW9662 and pioglitazone were applied to inhibit and activate the PPARγ, respectively. Enzyme-linked immunoassays were used to detect inflammatory cytokines. The expressions of miR-129-5p, the PPARγ, and the autophagy-marker protein were detected by quantitative polymerase chain reaction (qPCR) or Western blot. Dual-luciferase reporter assays were used to verify the targeting relationship between miR-129-5p and PPARγ messenger RNA (mRNA). Human lung epithelial cells BEAS-2B transfected with the miR-129-5p inhibitor and/or the short interfering RNA PPARγ (si-PPARγ) were applied to explore the mechanism. Results: The results showed that pioglitazone promoted autophagy and relieved lung injury caused by LPS, while GW9662 exacerbated lung injury. MiR-129-5p directly targeted the PPARγ. Inhibiting the expression of miR-129-5p increased the level of the PPARγ, induced autophagy, and inhibited apoptosis and the inflammatory response. Conversely, silencing the PPARγ had the opposite effects, and blocked the protective effects of the miR-129-5p inhibitor. Conclusions: The inhibition of miR-129-5p may induce autophagy and inhibit the inflammatory response by promoting the expression of the PPARγ, thereby relieving ARDS.
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Objective: We aimed to evaluate and compare the association between globulin to albumin ratio (GAR) and globulin to prealbumin ratio (GPR) and 3-month functional prognosis of acute ischemic stroke (AIS) patients receiving intravenous thrombolysis therapy. Methods: 234 AIS patients undergoing intravenous thrombolysis were retrospectively enrolled with acute ischemic stroke from February 2016 to October 2019. Blood sample was collected within 24 h after admission. Poor outcome was defined as the modified Rankin Scale (mRS) ≥ 3 and a favorable outcome as mRS < 3. Severe stroke was defined as the National Institutes of Health Stroke Scale (NIHSS) score > 10 on admission. Student's t-test, Mann-Whitney U test, Chi-square test, logistics' regression analysis, and receiver operating characteristic (ROC) analysis were performed. Results: Patients with poor functional outcome had higher GAR and GPR levels compared with favorable functional group (p = 0.001, p < 0.001, respectively). Severe stroke was also associated with these two increasing variables. After adjustment for confounding factors, multivariate logistic regression analysis indicated that GPR was an independent indicator predictor of AIS. Conclusions: The 24 h GPR level can predict the 3-month functional outcome in AIS patients accepting recombinant tissue plasminogen activator (r-tPA) intravenous thrombosis.