Harnessing TME depicted by histological images to improve cancer prognosis through a deep learning system.

Spatial transcriptomics (ST) provides insights into the tumor microenvironment (TME), which is closely associated with cancer prognosis, but ST has limited clinical availability. In this study, we provide a powerful deep learning system to augment TME information based on histological images for patients without ST data, thereby empowering precise cancer prognosis. The system provides two connections to bridge existing gaps. The first is the integrated graph and image deep learning (IGI-DL) model, which predicts ST expression based on histological images with a 0.171 increase in mean correlation across three cancer types compared with five existing methods. The second connection is the cancer prognosis prediction model, based on TME depicted by spatial gene expression. Our survival model, using graphs with predicted ST features, achieves superior accuracy with a concordance index of 0.747 and 0.725 for The Cancer Genome Atlas breast cancer and colorectal cancer cohorts, outperforming other survival models. For the external Molecular and Cellular Oncology colorectal cancer cohort, our survival model maintains a stable advantage.

Lipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis.

Oxidative stress-induced lipid accumulation is mediated by lipid droplets (LDs) homeostasis, which sequester vulnerable unsaturated triglycerides into LDs to prevent further peroxidation. Here we identify the upregulation of lipopolysaccharide-binding protein (LBP) and its trafficking through LDs as a mechanism for modulating LD homeostasis in response to oxidative stress. Our results suggest that LBP induces lipid accumulation by controlling lipid-redox homeostasis through its lipid-capture activity, sorting unsaturated triglycerides into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated triglycerides accumulation by phospholipid/triglycerides competition and Peroxiredoxin 4, a redox state sensor of LBP that regulates the shuttle of LBP from LDs. Furthermore, chronic stress upregulates LBP expression, leading to insulin resistance and obesity. Our findings contribute to the understanding of the role of LBP in regulating LD homeostasis and against cellular peroxidative injury. These insights could inform the development of redox-based therapies for alleviating oxidative stress-induced metabolic dysfunction.

Association between blood heavy metals and lung cancer risk: A case-control study in China.

BACKGROUND: Exposure to various metals has been reported to lead to lung cancer. However, few studies focused on the combined effects of metal mixture. OBJECTIVE: To explore the relationship between metal mixture and lung cancer patients. METHODS: Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure the concentration of 8 heavy metals (V, Cr, Mn, Se, Mo, Cd, Ba and Pb) in serum samples of 86 cases and 105 controls in the Tianjin Lung Cancer Cohort. Logistic regression models were used to estimate the effect of each metal on the risk of lung cancer. The restricted cubic spline function was applied to describe the dose-response relationship between various metal concentrations and lung cancer risk. Bayesian Kernel Machine Regression (BKMR), Weighted Quantile Sum (WQS) and Quantile G-Computation (QGC) were employed to explore the effects of metal mixtures as a whole on lung cancer. RESULTS: An increased risk of lung cancer was associated with higher blood Mo concentration (adjusted OR = 2.94, 95% CI = 1.03-8.74 for tertile 2 vs. tertile 1). Higher Se concentration in blood may have protective effects on the risk of lung cancer (adjusted OR = 0.18, 95% CI = 0.06-0.51 for tertile 3 vs. tertile 1, p-trend <0.001). In addition, Se and Cd may have an antagonism effect on the occurrence of lung cancer (RERI and 95% CI = -0.95 [-31.77, -0.07]; AP and 95% CI = -0.95 [-5.16 -0.74]). Although the metal mixture did not show a significant effect on lung cancer as a whole, this may be due to the offsetting effect between positive and negative effects. CONCLUSIONS: Our research indicates that Se has a promising anti-cancer application, but it is necessary to prevent the role of Cd that antagonize Se in lung cancer.

Current understanding of the contribution of lactate to the cardiovascular system and its therapeutic relevance.

Research during the past decades has yielded numerous insights into the presence and function of lactate in the body. Lactate is primarily produced via glycolysis and plays special roles in the regulation of tissues and organs, particularly in the cardiovascular system. In addition to being a net consumer of lactate, the heart is also the organ in the body with the greatest lactate consumption. Furthermore, lactate maintains cardiovascular homeostasis through energy supply and signal regulation under physiological conditions. Lactate also affects the occurrence, development, and prognosis of various cardiovascular diseases. We will highlight how lactate regulates the cardiovascular system under physiological and pathological conditions based on evidence from recent studies. We aim to provide a better understanding of the relationship between lactate and cardiovascular health and provide new ideas for preventing and treating cardiovascular diseases. Additionally, we will summarize current developments in treatments targeting lactate metabolism, transport, and signaling, including their role in cardiovascular diseases.

Association of statin use and increase in lipoprotein(a): a real-world database research.

BACKGROUND: There is an increased concern that statins may have an unintended effect of elevated lipoprotein(a) [Lp(a)]. We conducted a large sample real-world study to test the association. METHODS: This retrospective cohort study was conducted using data from an integrated SuValue database, which includes 221 hospitals across China covering more than 200,000 of population with longitudinal follow-up to 10 years. Propensity score matching was applied to identify two comparable cohorts with statin users and non-statin users. Detailed follow-up information such as Lp(a) levels were extracted. The hazard ratio was calculated on Lp(a) changes based on the statin usage cohorts. Detailed subgroup and different characteristic cohorts' analyses were also conducted. RESULTS: After baseline propensity score matching, a total of 42,166 patients were included in a 1:1 matched ratio between statin users and non-statin users. In the case of no difference in low density lipoprotein (LDL-C), Lp(a) was increased significantly with the use of statins (adjusted HR 1.47; 95% confidence interval [CI] 1.43-1.50). Lp(a) increase was observed in various subgroup analyses and different cohorts. The dose intensity of statin was positively associated with the evaluated Lp(a) level. CONCLUSION: The use of statins was associated with an increased risk of Lp(a) elevation compared with non-statin use counterparts. The clinical relevance of these increases needs to be addressed in surrogate marker trials and/or large, cardiovascular outcomes trials.

Differences in right ventricular function and response to targeted therapy between patients with IPAH and PAH-CHD.

Background and aims: Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disorder characterized by elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). Right heart failure is a life-threatening complication of PAH and predicts a poor prognosis. PAH associated with congenital heart disease (PAH-CHD) and idiopathic PAH (IPAH) are two prevalent PAH subtypes in China. In this section, we set out to explore baseline right ventricular (RV) function and its response to targeted agents between IPAH and PAH-CHD. Methods and results: Consecutive patients diagnosed with IPAH or PAH-CHD by right heart catheterization (RHC) in the Second Xiangya Hospital from November 2011 to June 2020 were included. All patients received PAH-targeted therapy and the RV function was assessed by echocardiography at baseline and during follow-up. A total of 303 patients (age, 36.23 ± 13.10 years; women, 213 (70.3%); mean PAP [mPAP], 63.54 ± 16.12 mmHg; PVR, 14.74 ± 7.61 WU) with IPAH (n = 121) or PAH-CHD (n = 182) were included in this study. Compared with PAH-CHD, patients with IPAH had worse baseline RV function. As of the latest follow-up, forty-nine patients with IPAH and six patients with PAH-CHD died. Kaplan-Meier analyses showed better survival in PAH-CHD versus IPAH. After PAH-targeted therapy, patients with IPAH had less improvement in 6 MWD, World Health Organization functional class, and RV functional parameters compared with patients with PAH-CHD. Conclusion: Compared with patients with PAH-CHD, patients with IPAH had worse baseline RV function, unfavourable prognosis, and inadequate response to targeted treatment.

Multi-omics profiling of papillary thyroid microcarcinoma reveals different somatic mutations and a unique transcriptomic signature.

BACKGROUND: Papillary thyroid microcarcinoma (PTMC) incidence has significantly increased, and some cases still exhibit invasive traits. The entire molecular landscape of PTMC, which can offer hints for the etiology of cancer, is currently absent. METHODS: We compared our findings with those for PTMC in the TCGA by analyzing the largest study at the current stage of whole exome sequencing and RNA-sequencing data from 64 patients with PTMC. Then, we systematically demonstrated the differences between the two PTMC subtypes based on multi-omics analyses. Additionally, we created a molecular prediction model for the PTMC subtypes and validated them among TCGA patients for individualized integrative assessment. RESULTS: In addition to the presence of BRAF mutations and RET fusions in the TCGA cohort, we also discovered a new molecular signature named PTMC-inflammatory that implies a potential response to immune intervention, which is enriched with AFP mutations, IGH@-ext fusions, elevated immune-related genes, positive peroxidase antibody, and positive thyroglobulin antibody. Additionally, a molecular prediction model for the PTMC-inflammatory patients was created and validated among TCGA patients, while the prognosis for these patients is poor. CONCLUSIONS: Our findings comprehensively define the clinical and molecular features of PTMC and may inspire new therapeutic hypotheses.

Super-assembly of integrated gold magnetic assay with loop-mediated isothermal amplification for point-of-care testing.

With the increasing global threat of various diseases and infections, it is essential to develop a fast, low-cost, and easy-to-use point-of-care testing (POCT) system for inspections at all levels of medical institutions and self-examination at home. In this work, gold magnetic nanoparticles (GMNPs) are used as the key material, and a rapid visual detection method is designed through integrating loop-mediated isothermal amplification (LAMP) and lateral flow assay (LFA) biosensor for detecting a variety of analytes which includes whole blood, buccal swabs, and DNA. It is worth to note that the proposed method does not need DNA extraction. Furthermore, uracil DNA glycosylase (UDG) is employed to eliminate carrier contamination for preventing false positive results. The whole detection process can be finished within 25 min. The accuracy of detection is measured by assessing the polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) C677T. The detection limit of the newly developed extraction-free detection system for MTHFR C677T is 0.16 ng/µL. A preliminary clinical study of the proposed method is carried out by analyzing 600 clinical samples (including 200 whole blood samples, 100 buccal swabs, and 300 genomic DNA samples). The results indicate that the proposed method is 100% consistent with the sequencing results which provides a new choice for POCT and shows a broad application prospect in all levels of medical clinics and at home. Electronic Supplementary Material: Supplementary material (details for MTHFR C677T primer sequences, the cell count results of samples at different dilution ratios, genotyping results and frequency samples, a Hardy-Weinberg equilibrium test, the sensitivity of the system, detection results of multiple samples, and optimization of the system) is available in the online version of this article at 10.1007/s12274-022-4692-9.

D-Limonene inhibits the occurrence and progression of LUAD through suppressing lipid droplet accumulation induced by PM2.5 exposure in vivo and in vitro.

BACKGROUND: PM2.5 exposure is associated with lung adenocarcinoma (LUAD), but the mechanism is unclear. The lack of understanding impedes our effort on prevention. This study examined a possible mechanism of lung cancer caused by PM2.5 exposure, and aimed to find a potential intervention for people living in PM2.5 polluted regions. METHODS: Electron microscopy and oil-red staining were conducted to examine the lipid droplet accumulation. Masson's trichrome staining, colony forming, scratch assay and transwell experiment were conducted to evaluate the effect of PM2.5 exposure and D-limonene intervention on the occurrence and progression of LUAD. Potential intervention targets were found by RNA-Seq and verified by luciferase reporter assay. MiR-195 KO mice constructed with CRISPR/Cas9 technology were used to investigate the pivotal role of D-limonene-miR-195-SREBP1/FASN axis. Cohort analysis of lung cancer patients, human LUAD tissues staining and human intervention trial were also conducted to validate the results of cell and animal experiments. RESULTS: Our results showed that PM2.5 exposure induced accumulation of lipid droplets in LUAD cells which accompanied by increased malignant cellular behaviors. PM2.5 exposure led to cleaved N-SREBP1 translocation into nucleus, which activated the de novo lipogenesis pathway. Same changes were also observed in normal lung epithelial cells and normal lung tissue, and mice developed pulmonary fibrosis after long-term exposure to PM2.5. Furthermore, in a cohort of 11,712 lung cancer patients, significant lipid metabolism disorders were observed in higher PM2.5 polluted areas. In view of that, D-limonene was found to inhibit the changes in lipid metabolism through upregulating the expression of miR-195, which inhibited the expression of lipogenic genes (SREBF1/FASN/ACACA) specifically. And a small human intervention trial showed that serum miR-195 was upregulated after oral intake of D-limonene. CONCLUSION: Our findings reveal a new mechanism of pulmonary fibrosis and LUAD that is related to PM2.5 exposure-induced lipid droplet accumulation. We also demonstrate that D-limonene-miR-195-SREBP1/FASN axis is a potential preventive intervention for mediating the progression and development of LUAD induced by PM2.5 exposure. Trial registration Chinese Clinical Trial Registry, ChiCTR2000030200. Registered 25 February 2020, http://www.chictr.org.cn/showproj.aspx?proj=48013.

Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: A meta-analysis of Randomized-Controlled Trials.

BACKGROUND: Previous meta-analyses of pulmonary arterial hypertension (PAH) combination therapy pooled sequential and initial combination together, which might threaten their authenticity and clinical significance for the difference between two strategies. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sequential combination therapy (SCT) with background therapy (BT) in PAH patients. Raw data were extracted to calculate risk ratio (RR) or weighted mean difference (WMD) for predefined efficacy and safety outcomes. Mantel-Haenszel fixed or random effects model was used based on heterogeneity. RESULTS: 17 RCTs involving 4343 patients (97.2% of patients with WHO-FC II-III) were included. SCT decreased clinical worsening (RR 0.66, 95% CI 0.58 to 0.76), nonfatal clinical worsening (RR 0.61, 95% CI 0.52 to 0.71), functional class (decrease of 28% in the portion of patients with WHO-FC worsening and increase of 33% in the portion of patients with WHO-FC improvement), and increased 6-min walk distance (WMD 17.68 m, 95% CI 10.16 to 25.20), but didn't reduce mortality, lung transplantation, admission to hospital, and treatment escalation compared with BT. Although any adverse event and serious adverse event were similar between SCT and BT, SCT increased all-cause treatment discontinuation (RR 1.49, 95% CI 1.30 to 1.71) and drug-related treatment discontinuation (RR 2.30, 95% CI 1.86 to 2.84) with higher incidence of headache, flushing, nausea, diarrhoea and jaw pain. CONCLUSIONS: For WHO-FC II-III PAH patients who have established BT, our study reinforced the recommendation of SCT to improve clinical worsening, functional status, and exercise capacity, although with higher incidence of side-effects and withdrawal.

Hemin with Peroxidase Activity Can Inhibit the Oxidative Damage Induced by Ultraviolet A.

Excessive reactive oxygen species (ROS), a highly reactive substance that contains oxygen, induced by ultraviolet A (UVA) cause oxidative damage to skin. We confirmed that hemin can catalyze the reaction of tyrosine (Tyr) and hydrogen peroxide (H2O2). Catalysis was found to effectively reduce or eliminate oxidative damage to cells induced by H2O2 or UVA. The scavenging effects of hemin for other free-radical ROS were also evaluated through pyrogallol autoxidation, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·)-scavenging assays, and phenanthroline-Fe2+ assays. The results show that a mixture of hemin and tyrosine exhibits strong scavenging activities for H2O2, superoxide anion (O2-·), DPPH·, and the hydroxyl radical (·OH). Furthermore, the inhibition of oxidative damage to human skin keratinocyte (HaCaT) cells induced by H2O2 or UVA was evaluated. The results show that catalysis can significantly reduce the ratio of cell apoptosis and death and inhibit the release of lactate dehydrogenase (LDH), as well as accumulation of malondialdehyde (MDA). Furthermore, the resistance to apoptosis was found to be enhanced. These results show that the mixture of hemin and tyrosine has a significantly protective effect against oxidative damage to HaCaT cells caused by UVA, suggesting it as a protective agent for combating UVA damage.

Role of Gut Microbiota in Pulmonary Arterial Hypertension.

Gut microbiota and its metabolites play an important role in maintaining host homeostasis. Pulmonary arterial hypertension (PAH) is a malignant clinical syndrome with a frightening mortality. Pulmonary vascular remodeling is an important feature of PAH, and its pathogenesis is not well established. With the progress of studies on intestinal microbes in different disease, cumulative evidence indicates that gut microbiota plays a major role in PAH pathophysiology. In this review, we will systematically summarize translational and preclinical data on the correlation between gut dysbiosis and PAH and investigate the role of gut dysbiosis in the causation of PAH. Then, we point out the potential significance of gut dysbiosis in the diagnosis and treatment of PAH as well as several problems that remain to be resolved in the field of gut dysbiosis and PAH. All of this knowledge of gut microbiome might pave the way for the extension of novel pathophysiological mechanisms, diagnosis, and targeted therapies for PAH.

Dapagliflozin, sildenafil and their combination in monocrotaline-induced pulmonary arterial hypertension.

BACKGROUND: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH). METHODS: A monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments. RESULTS: Dapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) in plasma. However, dapagliflozin as an add-on therapy to sildenafil in rats with PAH did not show a more pronounced beneficial effect on right ventricular systolic pressure and pulmonary vascular remodelling in MCT rats than sildenafil alone. CONCLUSIONS: Dapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of PAH. However, combination therapy with dapagliflozin and sildenafil was not more effective than monotherapy with sildenafil in PAH rats.

A Novel Signature of Lipid Metabolism-Related Gene Predicts Prognosis and Response to Immunotherapy in Lung Adenocarcinoma.

Background: Lipid metabolism disorder, a new hallmark of cancer initiation, has been involved in lung adenocarcinoma (LUAD). However, few biomarkers about lipid metabolism-related genes (LMRGs) have been developed for prognosis prediction and clinical treatment of LUAD patients. Methods: In this study, we constructed and validated an effective prognostic prediction model for LUAD patients depending on LMRGs. Subsequently, we investigated the prediction model from immune microenvironment, genomic changes, and immunotherapy. Results: Then, eleven LMRGs were identified and applied to LUAD subtyping. In comparison with the high-risk group, the low-risk group exhibited a remarkably favorable prognosis, along with a higher immune score and lower tumor purity. Moreover, the low-risk group presented higher levels of immune checkpoint molecules, lower tumor immune dysfunction and exclusion (TIDE) score and tumor mutation burden (TMB), and higher likelihood of benefiting from immunotherapy. Furthermore, the genomic changes of six LMRGs (CD79A, HACD1, CYP17A1, SLCO1B3, ANGPTL4, and LDHA) were responsible for the difference in susceptibility to LUAD by greatly influencing B-cell activation. Conclusion: Generally speaking, the LMRG model is a reliable independent biomarker for predicting adverse outcomes in LUAD patients and has the potential to facilitate risk-stratified immunotherapy.

Stratification of lung adenocarcinoma patients for d-limonene intervention based on the expression signature genes.

Globally, lung cancer ranks as the most lethal malignant neoplasm. d-Limonene, a plant extract enriched with essential oils, has been reported to exert anti-cancer effects both in vitro and in vivo; however, its clinical effect on humans remains elusive. Therefore, the present study aimed to investigate the gene expression signature that would potentially stratify lung adenocarcinoma (LUAD) patients who may benefit from d-limonene intervention, thus facilitating the development of newer treatment strategies for LUAD. In total, 1877 significant differentially expressed genes (DEGs) were identified. These genes were mainly associated with the metabolism of terpenoids and polyketides, lipid metabolism, endocrine system, carbohydrate metabolism, and cell growth and death pathways. Three genes, including antioncogenes FZD3 and MTURN, and oncogene PRC1, which were regulated by d-limonene were identified based on survival analysis of TCGA-LUAD data and were validated by both in vitro and in vivo experiments. High-risk patients screened by the model exhibited a significantly poor prognosis. In conclusion, three gene expression signatures (FZD3, MTURN, and PRC1) were validated by both in vitro and in vivo experiments and identified to help stratify candidate lung adenocarcinoma patients who may benefit from d-limonene intervention. Although further studies are warranted, this study highlighted a potential strategy to improve the treatment outcomes of LUAD patients.

Transcriptome Based Estrogen Related Genes Biomarkers for Diagnosis and Prognosis in Non-small Cell Lung Cancer.

BACKGROUND: Lung cancer is the tumor with the highest morbidity and mortality, and has become a global public health problem. The incidence of lung cancer in men has declined in some countries and regions, while the incidence of lung cancer in women has been slowly increasing. Therefore, the aim is to explore whether estrogen-related genes are associated with the incidence and prognosis of lung cancer. METHODS: We obtained all estrogen receptor genes and estrogen signaling pathway genes in The Cancer Genome Atlas (TCGA), and then compared the expression of each gene in tumor tissues and adjacent normal tissues for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) separately. Survival analysis was performed of the differentially expressed genes in LUAD and LUSC patients separately. The diagnostic and prognostic values of the candidate genes were validated in the Gene Expression Omnibus (GEO) datasets. RESULTS: We found 5 estrogen receptor genes and 66 estrogen pathway genes in TCGA. A total of 50 genes were differently expressed between tumor tissues and adjacent normal tissues and 6 of the 50 genes were related to the prognosis of LUAD in TCGA. 56 genes were differently expressed between tumor tissues and adjacent normal tissues and none of the 56 genes was related to the prognosis of LUSC in TCGA. GEO datasets validated that the 6 genes (SHC1, FKBP4, NRAS, PRKCD, KRAS, ADCY9) had different expression between tumor tissues and adjacent normal tissues in LUAD, and 3 genes (FKBP4, KRAS, ADCY9) were related to the prognosis of LUAD. CONCLUSIONS: The expressions of FKBP4 and ADCY9 are related to the pathogenesis and prognosis of LUAD. FKBP4 and ADCY9 may serve as biomarkers in LUAD screening and prognosis prediction in clinical settings.

Identification of the EMT-Related Genes Signature for Predicting Occurrence and Progression in Thyroid Cancer.

BACKGROUND: The detection rate of thyroid cancer (TC) has been continuously improved due to the development of detection technology. Epithelial-mesenchymal transition (EMT) is thought to be closely related to the malignant progression of tumors. However, the relationship between EMT-related genes (ERGs) characteristics and the diagnosis and prognosis of TC patients has not been studied. METHODS: Four datasets from Gene Expression Omnibus (GEO) were used to perform transcriptomic profile analysis. The overlapping differentially expressed ERGs (DEERGs) were analyzed using the R package "limma". Then, the hub genes, which had a higher degree, were identified by the protein-protein interaction (PPI) network. Gene expression analysis between the TC and normal data, the disease-free survival (DFS) analysis of TC patients from The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA) cohort, function analysis, and immunohistochemistry (IHC) were performed to verify the importance of the hub genes. Finally, a prognostic risk scoring was constructed to predict DFS in patients with the selected genes. RESULTS: A total of 43 DEERGs were identified and 10 DEERGs were considered hub ERGs, which had a high degree of connectivity in the PPI network. Then, the differential expressions of FN1, ITGA2, and KIT between TC and normal tissues were verified in the TCGA-THCA cohort and their protein expressions were also verified by IHC. DFS analysis indicated upregulations of FN1 expression (P<0.01) and ITGA2 expression (P<0.01) and downregulation of KIT expression (P=0.01) increased risks of decreased DFS for TCGA-THCA patients. Besides, by building a prognostic risk scoring model, we found that the DFS of TCGA-THCA patients was significantly worse in high-risk groups. CONCLUSION: In summary, these hub ERGs were potential biomarkers for diagnosis and prognosis of TC, which can provide a basis for further exploring the efficacy of EMT in patients with TC.

Association between sex hormones regulation-related SNP rs12233719 and lung cancer risk among never-smoking Chinese women.

BACKGROUND: The mechanism of rapidly increased non-small cell lung cancer (NSCLC) among never-smoking Chinese women has not been elucidated. Ovarian sex steroid hormones have been suggested to counteract lung cancer development, and sex hormone-binding globulin (SHBG) is essential in sex hormones regulation. This study aims to exploring single nucleotide polymorphisms (SNPs) in genomic regions associated with SHBG concentrations that contributed to never-smoking female NSCLC. METHODS: Candidate genes were selected by a genome-wide association (GWAS) meta-analysis and gene expression profiles of never-smoking NSCLC of Chinese women. The candidate SNPs limited to common minor allele frequency (MAF), missense variant, ethnic heterogeneous distribution, and SNPs were genotyped using the TaqMan method. A two-stage case-control design was adopted for exploration and validation of associations between candidate SNPs and risk of NSCLC. All participants were never-smoking Chinese women. Chi-square test and multivariate logistic regression were applied. RESULTS: Beginning with 12 genomic regions associated with circulating SHBG concentrations and gene expression profiles from never-smoking NSCLC in Chinese women, candidate SNP rs12233719 and rs7439366 both located in candidate gene UGT2 B7, which may be related to circulating SHBG concentrations and cancer risk, were identified. A two-stage case-control study was conducted in Shenyang and Tianjin represented as the training stage and validation stage, respectively. Under the dominant model, compared to individuals with the wild G/G genotype, the adjusted OR of those with the T allele was 1.58 (95% CI: 1.15-2.16) in Chinese Shenyang training set, and was 1.49 (95% CI: 1.02-2.18) in Chinese Tianjin validation set, both accompanied with a significant trend relationship consistently. UGT2B7 was upregulated in female NSCLC patients' tumor tissues and was associated with a poor prognosis in NSCLC. CONCLUSION: Our findings indicated that a sex hormones regulation-related SNP rs12233719 was associated with never-smoking female lung cancer risk, which might partially explain NSCLC-susceptibility in Chinese women.

Expression of ApoA5 and its function in the right ventricular failing and remodeling secondary to pulmonary hypertension.

Right heart failure and right ventricular (RV) remodeling were the main reason for mortality of pulmonary hypertension (PH) patients. Apolipoprotein AV (ApoA5) is a key regulator of plasma triglyceride and have multifunction in several target organs. We detected decreased ApoA5 in serum of patients with PH and both in serum and RV of monocrotaline-induced PH model. Exogenously, overexpression ApoA5 by adenovirus showed protective effects on RV failure and RV fibrosis secondary to PH. In addition, in vitro experiments showed ApoA5 attenuated the activation of fibroblast induced by transforming growth factor ß1 and synthesis and secretion of extracellular matrix by inhibiting focal adhesion kinase-c-Jun N-terminal kinase-Smad3 pathway. Finally, we suggest that ApoA5 may potentially be a pivotal target for RV failure and fibrosis secondary of PH.