Clinical characteristics of patients with a risk of pulmonary artery hypertension secondary to ARDS in a high-altitude area.

BACKGROUND: Hypoxaemia plays an important role in the development of pulmonary artery hypertension (PAH). Patients with acute respiratory distress syndrome (ARDS) in a high-altitude area have different pathophysiological characteristics from those patients in the plains. The goal of our study was to explore the clinical characteristics of PAH secondary to ARDS in a high-altitude area. METHODS: This was a prospective study conducted in the affiliated Hospital of Qinghai University. Two investigators independently assessed pulmonary artery pressure (PAP) and right ventricular function by transthoracic echocardiography. Basic information and clinical data of the patients who were enrolled were collected. A multivariable logistic regression model was used to evaluate the risk factors for PAH secondary to ARDS in the high-altitude area. RESULTS: The incidence of PAH secondary to ARDS within 48 hours in the high-altitude area was 44.19%. Partial pressure of oxygen/fraction of inspired oxygen <165.13 mm Hg was an independent risk factor for PAH secondary to ARDS in the high-altitude area. Compared with the normal PAP group, the right ventricular basal dimensions were significantly larger and the right ventricular tricuspid annular plane systolic excursion was lower in the PAH group (right ventricular basal dimensions: 45.47±2.60 vs 40.67±6.12 mm, p=0.019; tricuspid annular plane systolic excursion (TAPSE): 1.82±0.40 vs 2.09±0.32 cm, p=0.021). The ratio of TAPSE to systolic PAP was lower in the PAH group (0.03±0.01 vs 0.08±0.03 cm/mm Hg, p<0.001). CONCLUSIONS: The incidence of PAH in patients with ARDS in our study is high. PAH secondary to ARDS in a high-altitude area could cause right ventricular dysfunction. TRIAL REGISTRATION NUMBER: NCT05166759.

Suggestive evidence of CYP4F2 gene polymorphisms with HAPE susceptibility in the Chinese Han population.

High altitude pulmonary edema (HAPE) is a common respiratory disease in the high altitude area, which is rapid and harmful. We firstly conducted a case-control study to assess the potential association of CYP4F2 gene polymorphisms with HAPE susceptibility in the Chinese Han population. The study recruited 238 patients with HAPE and 230 healthy controls in Northwest China. Genomic DNA was extracted from blood samples, and gene polymorphisms were detected using the Agena MassARRAY platform. Odds ratios (ORs), 95% confidence intervals (95% CIs), and P-value were used to evaluate the relationship between HAPE risk and CYP4F2 gene polymorphisms. Multi-factor dimension reduction (MDR) was used to assess the optimal interaction of CYP4F2 gene polymorphisms on HAPE risk. We found rs3093193 was shown to reduce the risk of HAPE (OR = 0.70, 95% CI = 0.52-0.93, P = 0.014), while rs12459936 was increased the susceptibility to HAPE (OR = 2.08, 95% CI = 1.33-3.26, P = 0.001). Age stratified analysis revealed that rs3093193 and rs12459936 were correlated with HAPE risk in people at age > 32 years old, and rs3093193 and rs3093110 were correlated with the HAPE risk in people at age ≤ 32 years old. Gender stratification analysis was found that rs3093193, rs12459936, and rs3093110 were all related to HAPE risk in males. A combination of rs12459936 and rs3093110 was the best multi-loci model with the highest testing accuracy. Our study is the first to provide the association between CYP4F2 gene polymorphisms and HAPE risk in the Chinese Han population.

Definition of Acute Respiratory Distress Syndrome on the Plateau of Xining, Qinghai: A Verification of the Berlin Definition Altitude-PaO2/FiO2-Corrected Criteria.

Background: Acute respiratory distress syndrome (ARDS) is a common critical respiratory illness. Hypoxia at high altitude is a factor that influences the progression of ARDS. Currently, we lack clear diagnostic criteria for high-altitude ARDS. The purpose of this study was to determine the value of the application of the Berlin Definition altitude-PaO2/FiO2-corrected criteria for ARDS in Xining, Qinghai (2,261 m). Methods: We retrospectively analyzed the clinical data of patients with ARDS admitted to the Department of Critical Care Medicine of the Affiliated Hospital of Qinghai University from January 2018 to December 2018. The severity of ARDS was categorized according to the Berlin Definition, Berlin Definition altitude-PaO2/FiO2-corrected criteria, and the diagnostic criteria for acute lung injury (ALI)/ARDS at high altitudes in Western China (Zhang criteria). In addition, the differences between the three criteria were compared. Results: Among 1,221 patients, 512 were treated with mechanical ventilation. In addition, 253 met the Berlin Definition, including 49 (19.77%) with mild ARDS, 148 (58.50%) with moderate ARDS, and 56 (22.13%) with severe ARDS. A total of 229 patients met the altitude-PaO2/FiO2-corrected criteria, including 107 with mild ARDS (46.72%), 84 with moderate ARDS (36.68%), and 38 (16.59%) with severe ARDS. Intensive care unit (ICU) mortality increased with the severity of ARDS (mild, 17.76%; moderate, 21.43%; and severe, 47.37%). Twenty-eight-day mortality increased with worsening ARDS (mild 23.36% vs. moderate 44.05% vs. severe 63.16%) (p < 0.001). There were 204 patients who met the Zhang criteria, including 87 (42.65%) with acute lung injury and 117 (57.35%) with ARDS. The area under receiver operating characteristics (AUROCs) of the Berlin Definition, the altitude-P/F-corrected criteria, and the Zhang criteria were 0.6675 (95% CI 0.5866-0.7484), 0.6216 (95% CI 0.5317-0.7116), and 0.6050 (95% CI 0.5084-0.7016), respectively. There were no statistically significant differences between the three diagnostic criteria. Conclusion: For Xining, Qinghai, the altitude-PaO2/FiO2-corrected criteria for ARDS can distinguish the severity of ARDS, but these results need to be confirmed in a larger sample and in multicenter clinical studies. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04199650.

MIR17HG polymorphisms contribute to high-altitude pulmonary edema susceptibility in the Chinese population.

High-altitude pulmonary edema (HAPE) is a common acute altitude sickness. This study was designed to investigate the effect of MIR17HG polymorphisms on HAPE risk in the Chinese population. The Agena MassARRAY platform was used to genotype six single-nucleotide polymorphisms (SNPs) in the MIR17HG gene in 244 HAPE patients and 243 non-HAPE controls. The odds ratio (OR) and 95% confidence interval were used to evaluate the association between each MIR17HG polymorphisms and the risk of HAPE under a polygenetic model. Statistical analysis was performed using the χ2 test. Multifactor dimensionality reduction (MDR) analysis was used to analyze the impacts of SNP-SNP interactions on the risk of HAPE. According to the allele model, the HAPE risk of people with the rs7318578 A allele of MIR17HG was lower than that of people with the C allele (OR 0.74, p = 0.036).Logistic regression analysis of four models for all selected MIR17HG SNPs showed significant differences in the frequencies of rs7318578 (OR 0.74, p = 0.037) and rs17735387 (OR 1.51, p = 0.036) between cases and controls. The results of the sex stratification analysis showed that among males, rs17735387 in the MIR17HG gene is associated with an increased risk of HAPE. MDR analysis showed that the best combination model was a three-locus model incorporating rs72640334, rs7318578, and rs7336610. This study revealed the correlations between rs7318578 and rs17735387 on the MIR17HG gene and the risk of HAPE in the Chinese population, providing a theoretical basis for the early screening, prevention, and diagnosis of HAPE in high-risk populations.

Genetic variants in GHR and PLCE1 genes are associated with susceptibility to esophageal cancer.

BACKGROUND: Esophageal cancer (EC) is the leading cause of cancer-related mortality worldwide. The underlying genetic risk factors remain unclear. The association between gene growth hormone receptor (GHR) and phospholipase C epsilon 1 (PLCE1) polymorphisms and the EC risk were identified in this study. METHODS: A total of 506 EC cases and 507 controls were included in this research. Two SNPs (rs6898743 of GHR and rs2274223 of PLCE1) were selected and genotyped. The associations between gene polymorphisms and the EC risk were assessed by logistic regression analysis. The databases RegulomeDB, GTEx, and UALCAN were used for functional annotations. RESULTS: In the allelic frequencies analysis, the rs6898743 of GHR was associated with decreased susceptibility of EC (OR = 0.83, 95% CI: 0.70-1.00, p = 0.049), while rs2274223 of PLCE1 was associated with increased 0.25-fold EC risk (OR = 1.25, 95% CI: 1.02-1.53, p = 0.037). The "GC" genotype of rs6898743 was associated with a 0.24-fold decreased risk of EC under co-dominant model (OR = 0.76, 95% CI: 0.58-0.99, p = 0.046), and the "GA" genotype of rs2274223 was associated with increased EC risk under co-dominant model (OR = 1.36, 95% CI: 1.04-1.77, p = 0.023). Using GTEx database, rs2274223 was found to be significant associated with increased PLCE1 expression (p = 4.1 × 10-7 ) in esophagus muscularis. The UALCAN database demonstrated that the GHR gene was under-expressed in esophageal cancer tissues (p = 0.017). CONCLUSION: The gene GHR and PLCE1 polymorphisms are associated with EC in the general population and the results need to be verified in future.

CADM2, as a new target of miR-10b, promotes tumor metastasis through FAK/AKT pathway in hepatocellular carcinoma.

BACKGROUND: Cell adhesion molecules (CADMs) comprise of a protein family whose functions include maintenance of cell polarity and tumor suppression. Hypo-expression of CADM2 gene expression has been observed in several cancers including hepatocellular carcinoma (HCC). However, the role and mechanisms of CADM2 in HCC remain unclear. METHODS: The expression of CADM2 and miRNA-10b (miR-10b) in HCC tissues and cell lines were detected using real-time PCR and Western blotting. Immunofluorescence was used to detect Epithelial-mesenchymal transition (EMT) progression in HCC cell lines. Dual-luciferase reporter assay was used to determine miR-10b binding to CADM2 3'UTR. Wound healing assay and Transwell assay were performed to examine the migration and invasion of HCC cells. RESULTS: We report the effect of CADM2 as a tumor suppressor in HCC. Firstly, we confirmed that CADM2 expression was significantly down regulated in HCC tissues compared to normal tissues according to TCGA data analysis and fresh HCC sample detection. Secondly, overexpression of CADM2 could inhibit EMT process, migratory and invasion ability of HCC cells. Furthermore, the results indicated that CADM2 is a direct target of miR-10b in HCC cells and miR-10b/CADM2 modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC. CONCLUSIONS: Our study demonstrates that miR-10b-CADM2-FAK/AKT axis plays an important role in HCC metastasis, which might be a novel potential therapeutic option for HCC treatment.

Val66Met Polymorphism in BDNF Has No Sexual and APOE ε4 Status-Based Dimorphic Effects on Susceptibility to Alzheimer's Disease: Evidence From an Updated Meta-Analysis of Case-Control Studies and High-Throughput Genotyping Cohorts.

Some studies showed that Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) conveys susceptibility to Alzheimer's disease (AD) in females only. However, the confounding effects of some risk factors for AD were omitted in these studies. The aim of this meta-analysis comprising 19 604 patients with AD and 26 333 controls was to reexamine the association between Val66Met and AD by conditioning the effects of age, sex, and/or apolipoprotein E ( APOE) ε4 status. In agreement with the previous meta-analysis, Val66Met was associated with AD in females without confounding adjustment (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.03-1.14; P = .003). Nevertheless, after adjusting for age and APOE ε4 status, Val66Met was not associated with AD in females (OR, 1.02; 95% CI, 0.94-1.11; P = .57). This comprehensive meta-analysis with the largest sample size demonstrated no association could be observed between Val66Met and AD in general or by dividing samples based on sex or APOE ε4.

Heme oxygenase-1 prevents cardiac dysfunction in streptozotocin-diabetic mice by reducing inflammation, oxidative stress, apoptosis and enhancing autophagy.

Heme oxygenase-1 (HO-1) has been implicated in cardiac dysfunction, oxidative stress, inflammation, apoptosis and autophagy associated with heart failure, and atherosclerosis, in addition to its recognized role in metabolic syndrome and diabetes. Numerous studies have presented contradictory findings about the role of HO-1 in diabetic cardiomyopathy (DCM). In this study, we explored the role of HO-1 in myocardial dysfunction, myofibril structure, oxidative stress, inflammation, apoptosis and autophagy using a streptozotocin (STZ)-induced diabetes model in mice systemically overexpressing HO-1 (Tg-HO-1) or mutant HO-1 (Tg-mutHO-1). The diabetic mouse model was induced by multiple peritoneal injections of STZ. Two months after injection, left ventricular (LV) function was measured by echocardiography. In addition, molecular biomarkers related to oxidative stress, inflammation, apoptosis and autophagy were evaluated using classical molecular biological/biochemical techniques. Mice with DCM exhibited severe LV dysfunction, myofibril structure disarray, aberrant cardiac oxidative stress, inflammation, apoptosis, autophagy and increased levels of HO-1. In addition, we determined that systemic overexpression of HO-1 ameliorated left ventricular dysfunction, myofibril structure disarray, oxidative stress, inflammation, apoptosis and autophagy in DCM mice. Furthermore, serine/threonine-specific protein kinase (Akt) and AMP-activated protein kinase (AMPK) phosphorylation is normally inhibited in DCM, but overexpression of the HO-1 gene restored the phosphorylation of these kinases to normal levels. In contrast, the functions of HO-1 in DCM were significantly reversed by overexpression of mutant HO-1. This study underlines the unique roles of HO-1, including the inhibition of oxidative stress, inflammation and apoptosis and the enhancement of autophagy, in the pathogenesis of DCM.