Efficacy of early administration of sacubitril/valsartan after coronary artery revascularization in patients with acute myocardial infarction complicated by moderate-to-severe mitral regurgitation: a randomized controlled trial.

Effects of angiotensin receptor/neprilysin inhibitors (ARNI) on ventricular remodeling in patients with heart failure, especially heart failure with reduced ejection fraction (HFrEF), are better than those of angiotensin-converting enzyme inhibitors (ACEI). Acute myocardial infarction (AMI) complicated by mitral regurgitation exacerbates ventricular remodeling and increases the risk of heart failure. There is limited evidence on the effects of early administration of ARNI in patients with AMI complicated by mitral regurgitation. The aim of this trial was to examine the effectiveness and the safety of early administration of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation. This was a randomized, single-blind, parallel-group, controlled trial. From June 2021 to June 2022, we enrolled 142 consecutive patients with AMI complicated by moderate-to-severe mitral regurgitation and followed them for 12 months. The patients received standard treatment for AMI and were randomly assigned to receive ARNI or benazepril. The primary efficacy end points were the differences in mitral regurgitant jet area (MRJA), mitral regurgitant volume (MRV), concentration of n-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume and end-systolic volume (LVEDV and LVESV) between groups and within groups at baseline, 1, 3, 6, and 12 months. Secondary end points included the rates of heart failure hospitalization, all-cause mortality, refractory angina, malignant arrhythmias, recurrent myocardial infarction, and stroke. Safety end points included the rates of hyperkalemia, renal dysfunction, hypotension, angioedema, and cough. The ARNI group had significantly lower NT-proBNP levels than the benazepril group at 1 month and later (P < 0.001). MRJA and MRV significantly improved in the ARNI group compared with the benazepril group at 12 months (MRJA: - 3.21 ± 2.18 cm2 vs. - 1.83 ± 2.81 cm2, P < 0.05; MRV: - 27.22 ± 15.22 mL vs. - 13.67 ± 21.02 mL, P < 0.001). The ARNI group also showed significant reductions in LVEDV and LVESV (P < 0.05) and improvement in LVEF (P < 0.05). Secondary end point analysis showed a significantly higher rate of heart failure hospitalization in the benazepril group compared with the ARNI group (HR = 2.03, 95% CI 1.12-3.68, P = 0.021). Safety end point analysis showed a higher rate of hypotension in the ARNI group (P < 0.05). Early use of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation can significantly reduce mitral regurgitation, improve ventricular remodeling, and decrease heart failure hospitalization. Nevertheless, caution is needed to avoid hypotension. Chinese Clinical Trial Registry (ChiCTR2100054255) registered on December 11, 2021.

Advanced Progress of the Relationship Between Antihypertensive Drugs and Bone Metabolism.

Hypertension and osteoporosis are common comorbidities among elderly individuals. Drug therapy has been widely used in clinical practice as the preferred antihypertensive treatment. Therefore, antihypertensive drugs have become some of the most commonly prescribed drugs in healthcare settings. However, antihypertensive drugs have different effects on bone metabolism. The results of animal and clinical studies on the effects of antihypertensive drugs on osteoporosis or fracture risk are controversial and have aroused widespread concern among clinicians. Recent studies found that angiotensin receptor blockers, selective ß-adrenergic receptor blockers, and thiazide diuretics might improve bone trabecular number and bone mineral density by stimulating osteoblast differentiation, reducing osteoclast generation, and other mechanism. Furthermore, nonselective ß-adrenergic receptor blockers and dihydropyridine calcium channel blockers were found to have no significant relationship with bone mineral density or bone strength, and α-adrenergic receptor blockers and loop diuretics might increase fracture risk by decreasing bone mineral density. This article aimed to review previous animal experiments, clinical studies, and meta-analyses focusing on the effects of different antihypertensive drugs on bone metabolism, and to provide a new approach for the prevention and treatment of osteoporosis.

Identification of Key Biomarkers and Candidate Molecules in Non-Small-Cell Lung Cancer by Integrated Bioinformatics Analysis.

Background: Non-small cell lung cancer (NSCLC) is the most prevalent malignant tumor of the lung cancer, for which the molecular mechanisms remain unknown. In this study, we identified novel biomarkers associated with the pathogenesis of NSCLC aiming to provide new diagnostic and therapeutic approaches for NSCLC by bioinformatics analysis. Methods: From the Gene Expression Omnibus database, GSE118370 and GSE10072 microarray datasets were obtained. Identifying the differentially expressed genes (DEGs) between lung adenocarcinoma and normal samples was done. By using bioinformatics tools, a protein-protein interaction (PPI) network was constructed, modules were analyzed, and enrichment analyses were performed. The expression and prognostic values of 14 hub genes were validated by the GEPIA database, and the correlation between hub genes and survival in lung adenocarcinoma was assessed by UALCAN, cBioPortal, String and Cytoscape, and Timer tools. Results: We found three genes (PIK3R1, SPP1, and PECAM1) that have a clear correlation with OS in the lung adenocarcinoma patient. It has been found that lung adenocarcinoma exhibits high expression of SPP1 and that this has been associated with poor prognosis, while low expression of PECAM1 and PIK3R1 is associated with poor prognosis (P < 0.05). We also found that the expression of SPP1 was associated with miR-146a-5p, while the high expression of miR-146a-5p was related to good prognosis (P < 0.05). On the contrary, the lower miR-21-5p on upstream of PIK3R1 is associated with a higher surviving rate in cancer patients (P < 0.05). Finally, we found that the immune checkpoint genes CD274(PD-L1) and PDCD1LG2(PD-1) were also related to SPP1 in lung adenocarcinoma. Conclusions: The results indicated that SPP1 is a cancer promoter (oncogene), while PECAM1 and PIK3R1 are cancer suppressor genes. These genes take part in the regulation of biological activities in lung adenocarcinoma, which provides a basis for improving detection and immunotherapeutic targets for lung adenocarcinoma.

Exposure to famine in every stage of life and the risk of osteoporosis and fractures later in life: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Data on the association between early-life famine exposure and osteoporosis and fractures remain limited and inconclusive. The aim of this study was to investigate the correlation between famine exposure and osteoporosis and fractures. METHODS: We performed a cross-sectional analysis using the first follow-up survey data from the China Cardiometabolic Disease and Cancer Cohort Study from 2014 to 2016. We classified 4807 Lanzhou participants into seven groups based on their birthday (non-exposed or exposed in the fetal stage, early childhood, mid-childhood, late childhood, adolescence, or early adulthood). And we combined the non-exposed and early-adulthood exposed groups as a control group, which was called "age balanced group". This age-balanced group was used as the control group to further evaluate the risk of osteoporosis and fracture. We used multiple logistic regression to estimate the association between famine exposure and the risk of osteoporosis (T-score ≤ -1.8 by QUS) and self-reported fracture. RESULTS: In women, compared to the age-balanced group, the odds ratios (95 % CI) for the risk of osteoporosis were 1.400(1.034, 1.897), 1.630(1.268, 2.095), 1.707(1.314, 2.218), 2.150(1.732.2.668) and 2.885(2.286,3.641) in the fetal stage, early childhood, mid-childhood, late childhood and adolescence famine-exposed cohorts. In men, no association between famine and osteoporosis was noted with exposed cohort compared with the age-balanced control cohort (p > 0.05). Interestingly, the association between famine exposure and fractures was slightly different from the above results: in women, the odds ratios (95 % CI) for fractures in mid-childhood famine exposure was 1.461(1.082,1.973), in late childhood famine exposure was 1.333(1.035,1.718) and in adolescence famine exposure was 1.607(1.239,2.085). However, compared to the age-balanced control cohort, men exposed to famine in early childhood (OR: 1.801, 95 % CI: 1.010,3.211) had a higher risk of fracture. CONCLUSION: Famine exposure in different life stage has adverse effects on bone health. Famine exposure in not only the period from gestation to infancy, but also childhood and adolescence was associated with an increased risk of osteoporosis, especially in women. Exposure to famine in childhood- (mid and late) and adolescence- life period is associated with fracture in women. But, in men early-childhood famine exposure was only associated with fracture.

Convergent lines of evidence support BIN1 as a risk gene of Alzheimer's disease.

Genome-wide association studies (GWAS) have identified several susceptibility loci of Alzheimer's disease (AD), which were mainly located in noncoding regions of the genome. Meanwhile, the putative biological mechanisms underlying AD susceptibility loci were still unclear. At present, identifying the functional variants of AD pathogenesis remains a major challenge. Herein, we first used summary data-based Mendelian randomization (SMR) with AD GWAS summary and expression quantitative trait loci (eQTL) data to identify variants who affects expression levels of nearby genes and contributed to the risk of AD. Using the SMR integrative analysis, we totally identified 14 SNPs significantly affected the expression level of 16 nearby genes in blood or brain tissues and contributed to the AD risk. Then, to confirm the results, we replicated the GWAS and eQTL results across multiple samples. Totally, four risk SNP (rs11682128, rs601945, rs3935067, and rs679515) were validated to be associated with AD and affected the expression level of nearby genes (BIN1, HLA-DRA, EPHA1-AS1, and CR1). Besides, our differential expression analysis showed that the BIN1 gene was significantly downregulated in the hippocampus (P = 2.0 × 10-3) and survived after multiple comparisons. These convergent lines of evidence suggest that the BIN1 gene identified by SMR has potential roles in the pathogenesis of AD. Further investigation of the roles of the BIN1 gene in the pathogenesis of AD is warranted.

Correlation of serum vitamin D with lipid profiles in middle-aged and elderly Chinese individuals.

BACKGROUND AND OBJECTIVES: Deficiency of vitamin D has been associated with various health conditions. The purpose of this study was to evaluate the associations between the serum 25OHD concentration and lipid profiles in Chinese individuals. METHODS AND STUDY DESIGN: Serum 25OHD and lipid profiles were obtained for a cross sectional sample of 10100 individuals aged 40-75 years from Lanzhou city, which is located in western China. Linear-by-linear association, partial correlation analysis and multiple logistic regression analysis were used to evaluate associations between serum 25OHD concentration and lipid profiles. RESULTS: 10038 subjects aged 40- 75 years were included in the study. The 25OHD deficient and insufficient groups had higher TC, LDL-C and TG when compared to the optimal group. The dyslipidemia rates of vitamin D deficiency, insufficiency, and sufficiency groups were 45.4%, 41.6%, 38.8%, respectively. The prevalence rates of dyslipidemia, high cholesterol, high LDL-C, hypertriglyceridemia and mixed type hyperlipidemia exhibited decline trend in vitamin D deficiency, insufficiency and sufficiency groups. The correlation coefficients in between TC and 25OHD, LDL-C and 25OHD, TG and 25OHD were -0.033, -0.022, -0.044, respectively. Low 25OHD levels were associated with the risk of onset of dyslipidemia [OR 1.225 (95% CI 1.075-1.397), p=0.002] in the logistical regression analyses. CONCLUSIONS: Deficient serum 25OHD is associated with higher TC, LDL-C, and TG in middle-aged and elderly Chinese individuals. These findings suggest that low 25OHD levels observationally is simply a marker for elevated atherogenic lipoproteins and question a role for vitamin D supplementation in the prevention of cardiovascular disease.

Correction to: Identification of the targets of hematoporphyrin derivative in lung adenocarcinoma using integrated network analysis.

The Fig. 1b is wrongly published in the original publication of the article. The correct version of Fig. 1b is presented in this Correction.

Integrating genome-wide association study and expression quantitative trait loci data identifies NEGR1 as a causal risk gene of major depression disorder.

BACKGROUND: Genome-wide association studies (GWAS) have identified several genetic variants associated with major depression disorder (MDD). However, pinpointing the causal variants which are responsible for the association signal at a risk locus remains a major challenge. METHODS: We used Summary data-based Mendelian Randomization (SMR) with Psychiatric Genomics Consortium (PGC) GWAS summary and brain expression quantitative trait loci (eQTL) data to identify genes whose expression levels are causally associated with MDD. Then we performed differential expression analysis, methylation quantitative trait loci analysis, and cognitive genetics analysis to investigate the potential roles of risk genes in the pathogenesis of MDD. RESULTS: Through SMR integrative analysis, we identified the SNP rs10789336 located in Neuronal growth regulator 1 (NEGR1) gene significantly affected the expression level of RPL31P12 in brain tissues and contributed to the risk of MDD (P = 1.96 × 10-6). Consistently, the SNP rs10789336 was associated with the methylation levels of three nearby DNA methylation sites, including cg09256413 (NEGR1, P=1.72 × 10-10), cg11418303 (prostaglandin E receptor 3 [PTGER3], P = 4.78 × 10-6), and cg23032215 (ZRANB2 antisense RNA 2 [ZRANB2-AS2], P = 1.23 × 10-4). Differential expression analysis suggested that the NEGR1 gene was upregulated in prefrontal cortex (P = 5.14 × 10-3). Cognitive genetics analysis showed that the SNP rs10789336 was associated with cognitive performance (P = 2.41 × 10-16), educational attainment (P = 1.75 × 10-14), general cognitive function (P = 2.65 × 10-12), and verbal numerical reasoning (P = 1.36 × 10-12). CONCLUSION: Collectively, our results revealed that the SNP rs10789336 in NEGR1 might confer risk to MDD. Further investigation of the roles of NEGR1 in the pathogenesis of MDD is warranted.

Identification of the targets of hematoporphyrin derivative in lung adenocarcinoma using integrated network analysis.

BACKGROUND: Hematoporphyrin derivative (HPD) has a sensibilization effect in lung adenocarcinoma. This study was conducted to identify the target genes of HPD in lung adenocarcinoma. METHODS: RNA sequencing was performed using the lung adenocarcinoma cell line A549 after no treatment or treatment with X-ray or X-ray + HPD. The differentially expressed genes (DEGs) were screened using Mfuzz package by noise-robust soft clustering analysis. Enrichment analysis was carried out using "BioCloud" online tool. Protein-protein interaction (PPI) network and module analyses were performed using Cytoscape software. Using WebGestalt tool and integrated transcription factor platform (ITFP), microRNA target and transcription factor (TF) target pairs were separately predicted. An integrated regulatory network was visualized with Cytoscape software. RESULTS: A total of 815 DEGs in the gene set G1 (continuously dysregulated genes along with changes in processing conditions [untreated-treated with X-ray-X-ray + treated with HPD]) and 464 DEGs in the gene set G2 (significantly dysregulated between X-ray + HPD-treated group and untreated/X-ray-treated group) were screened. The significant module identified from the PPI network for gene set G1 showed that ribosomal protein L3 (RPL3) gene could interact with heat shock protein 90 kDa alpha, class A member 1 (HSP90AA1). TFs AAA domain containing 2 (ATAD2) and protein inhibitor of activated STAT 1 (PIAS1) were separately predicted for the genes in gene set G1 and G2, respectively. In the integrated network for gene set G2, ubiquitin-specific peptidase 25 (USP25) was targeted by miR-200b, miR-200c, and miR-429. CONCLUSION: RPL3, HSP90AA1, ATAD2, and PIAS1 as well as USP25, which is targeted by miR-200b, miR-200c, and miR-429, may be the potential targets of HPD in lung adenocarcinoma.

Identification of the targets of hematoporphyrin derivative in lung adenocarcinoma using integrated network analysis

BACKGROUND: Hematoporphyrin derivative (HPD) has a sensibilization effect in lung adenocarcinoma. This study was conducted to identify the target genes of HPD in lung adenocarcinoma. METHODS: RNA sequencing was performed using the lung adenocarcinoma cell line A549 after no treatment or treatment with X-ray or X-ray + HPD. The differentially expressed genes (DEGs) were screened using Mfuzz package by noise-robust soft clustering analysis. Enrichment analysis was carried out using "BioCloud" online tool. Protein-protein interaction (PPI) network and module analyses were performed using Cytoscape software. Using WebGestalt tool and integrated transcription factor platform (ITFP), microRNA target and transcription factor (TF) target pairs were separately predicted. An integrated regulatory network was visualized with Cytoscape software. RESULTS: A total of 815 DEGs in the gene set G1 (continuously dysregulated genes along with changes in processing conditions [untreated-treated with X-ray-X-ray + treated with HPD]) and 464 DEGs in the gene set G2 (significantly dysregulated between X-ray + HPD-treated group and untreated/X-ray-treated group) were screened. The significant module identified from the PPI network for gene set G1 showed that ribosomal protein L3 (RPL3) gene could interact with heat shock protein 90 kDa alpha, class A member 1 (HSP90AA1). TFs AAA domain containing 2 (ATAD2) and protein inhibitor of activated STAT 1 (PIAS1) were separately predicted for the genes in gene set G1 and G2, respectively. In the integrated network for gene set G2, ubiquitin-specific peptidase 25 (USP25) was targeted by miR-200b, miR-200c, and miR-429. CONCLUSION: RPL3, HSP90AA1, ATAD2, and PIAS1 as well as USP25, which is targeted by miR-200b, miR-200c, and miR-429, may be the potential targets of HPD in lung adenocarcinoma.

HGF induces EMT in non-small-cell lung cancer through the hBVR pathway.

The epithelial-to-mesenchymal transition (EMT) is a crucial event during non-small-cell lung cancer (NSCLC) invasion and metastasis. However, the mechanisms involved in NSCLC EMT have not been fully clarified. Hepatocyte growth factor (HGF) and human biliverdin reductase (hBVR) are reported to contribute to EMT in several diseases. Here, we show that compared with transforming growth factor beta (TGF-ß), fibroblast growth factor (FGF), and epidermal growth factor (EGF), HGF is an important cell factor for EMT in NSCLC cell lines A549 and H460. Met protein, HGF receptors, and hBVR were found to be highly expressed and positively correlated with EMT in NSCLC tissue sections. In addition, HGF and hBVR induced a decrease in epithelial protein marker expression and an increase in mesenchymal protein marker expression as well as increased cellular migration and invasion, indicating that both HGF and hBVR mediate EMT in A549 and H460 cell lines. Furthermore, HGF-induced EMT and migration and invasion in both cell lines was inhibited by si-hBVR. Taken together, our data show that HGF induces EMT in NSCLC through the hBVR pathway.