Knowledge-guided analysis of "omics" data using the KnowEnG cloud platform.

We present Knowledge Engine for Genomics (KnowEnG), a free-to-use computational system for analysis of genomics data sets, designed to accelerate biomedical discovery. It includes tools for popular bioinformatics tasks such as gene prioritization, sample clustering, gene set analysis, and expression signature analysis. The system specializes in "knowledge-guided" data mining and machine learning algorithms, in which user-provided data are analyzed in light of prior information about genes, aggregated from numerous knowledge bases and encoded in a massive "Knowledge Network." KnowEnG adheres to "FAIR" principles (findable, accessible, interoperable, and reuseable): its tools are easily portable to diverse computing environments, run on the cloud for scalable and cost-effective execution, and are interoperable with other computing platforms. The analysis tools are made available through multiple access modes, including a web portal with specialized visualization modules. We demonstrate the KnowEnG system's potential value in democratization of advanced tools for the modern genomics era through several case studies that use its tools to recreate and expand upon the published analysis of cancer data sets.

Associations among FT4 level, FT3/FT4 ratio, and non-alcoholic fatty liver disease in Chinese patients with hypopituitarism.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic metabolic disorder. Thyroid function is associated with NAFLD in different populations; however, little attention has been paid in patients with hypopituitarism. To analyze the association between thyroid function and NAFLD, we included 134 patients with hypopituitarism admitted to the Tianjin Medical University General Hospital between June 2013 and May 2019. Participants were divided into the NAFLD(-) and NAFLD(+) groups based on abdominal ultrasonography findings. We evaluated 68 male and 66 female patients with hypopituitarism. The prevalence of NAFLD was 52.24%. The NAFLD(+) group had a significantly higher free triiodothyronine/free thyroxine (FT3/FT4) ratio than the NAFLD(-) group (p = 0.003). The NAFLD(+) group showed significantly lower levels of FT4 and the growth hormone (GH) than the NAFLD(-) group (p = 0.003 and 0.016, respectively). We observed an association of the FT4 level and FT3/FT4 ratio with NAFLD in the univariate model, which was non-significant after adjustment for metabolic parameters (BMI, HDL-C, triglycerides, serum uric acid, blood pressure, fasting glucose). To better understand the role of each metabolic parameters, we performed additional models for each of those predictors individually after adjustment for age and gender, the association between FT4 level and FT3/FT4 ratio lost significance after adjustment for HDL-C and TG, but not for other predictors. Our findings suggest that thyroid dysfunction may be crucially involved in NAFLD by regulating whole-body metabolism, especially lipid utilization. Therefore, sufficient thyroid hormone replacement therapy for patients with hypopituitarism is recommended from the early stage.

SigMat: a classification scheme for gene signature matching.

Motivation: Several large-scale efforts have been made to collect gene expression signatures from a variety of biological conditions, such as response of cell lines to treatment with drugs, or tumor samples with different characteristics. These gene signature collections are utilized through bioinformatics tools for 'signature matching', whereby a researcher studying an expression profile can identify previously cataloged biological conditions most related to their profile. Signature matching tools typically retrieve from the collection the signature that has highest similarity to the user-provided profile. Alternatively, classification models may be applied where each biological condition in the signature collection is a class label; however, such models are trained on the collection of available signatures and may not generalize to the novel cellular context or cell line of the researcher's expression profile. Results: We present an advanced multi-way classification algorithm for signature matching, called SigMat, that is trained on a large signature collection from a well-studied cellular context, but can also classify signatures from other cell types by relying on an additional, small collection of signatures representing the target cell type. It uses these 'tuning data' to learn two additional parameters that help adapt its predictions for other cellular contexts. SigMat outperforms other similarity scores and classification methods in identifying the correct label of a query expression profile from as many as 244 or 500 candidate classes (drug treatments) cataloged by the LINCS L1000 project. SigMat retains its high accuracy in cross-cell line applications even when the amount of tuning data is severely limited. Availability and implementation: SigMat is available on GitHub at https://github.com/JinfengXiao/SigMat. Supplementary information: Supplementary data are available at Bioinformatics online.

Effects of electroacupuncture on reducing labor pain and complications in the labor analgesia process of combined spinal-epidural analgesia with patient-controlled epidural analgesia.

PURPOSE: To compare the pain scores and rates of complications in the labor analgesia process between the two groups. METHODS: There were 127 participants being recruited in this research, and randomly divided into 2 groups according to the anesthetic technique: CSEA with PCEA with EA group (group 1), CSEA with PCEA group (group 2). Group 1 was first operated CSEA and PCEA, then EA at Hegu (LI4), Neiguan (PC6), Zusanli (ST36) and Sanyinjiao (SP6) by HANS-200A device for 25 min. Group 2 was only treated by CSEA and PCEA. The main outcome was the VAS for labor pain. Meanwhile the complications, use of oxytocin, durations of three stages, delivery mode, cord blood pH and neonatus Apgar score in this study were considered as secondary outcomes. RESULTS: After labor analgesia, the VAS scores of group 1 at the five point-in-times were all lower than that of group 2. The rates of fever and urinary retention of group 1 were lower compared with group 2. Group 1 had less usage of oxytocin and shorter durations of cervical dilation from 3 to 10 cm and third stage than group 2. CONCLUSIONS: EA can help to reduce labor pain in CSEA with PCEA labor analgesia process, and may be able to reduce the complications.

DPPred: An Effective Prediction Framework with Concise Discriminative Patterns.

In the literature, two series of models have been proposed to address prediction problems including classification and regression. Simple models, such as generalized linear models, have ordinary performance but strong interpretability on a set of simple features. The other series, including tree-based models, organize numerical, categorical and high dimensional features into a comprehensive structure with rich interpretable information in the data. In this paper, we propose a novel Discriminative Pattern-based Prediction framework (DPPred) to accomplish the prediction tasks by taking their advantages of both effectiveness and interpretability. Specifically, DPPred adopts the concise discriminative patterns that are on the prefix paths from the root to leaf nodes in the tree-based models. DPPred selects a limited number of the useful discriminative patterns by searching for the most effective pattern combination to fit generalized linear models. Extensive experiments show that in many scenarios, DPPred provides competitive accuracy with the state-of-the-art as well as the valuable interpretability for developers and experts. In particular, taking a clinical application dataset as a case study, our DPPred outperforms the baselines by using only 40 concise discriminative patterns out of a potentially exponentially large set of patterns.

SSRP1 Contributes to the Malignancy of Hepatocellular Carcinoma and Is Negatively Regulated by miR-497.

The aim of this study is to clarify the clinical implication and functional role of structure specific recognition protein 1 (SSRP1) in hepatocellular carcinoma (HCC) and explore the underlying mechanism of aberrant high expression of SSRP1 in cancers. In the present investigation, we validated that SSRP1 was upregulated in HCC samples. We also demonstrated that its upregulation was associated with several clinicopathologic features such as higher serum AFP level, larger tumor size, and higher T stage of HCC patients; and its high expression indicated shorter overall survival and faster recurrence. To investigate the role of SSRP1 in HCC progression, both loss- and gain-function models were established. We demonstrated that SSPR1 modulated both proliferation and metastasis of HCC cells in vitro and vivo. Furthermore, we demonstrated that SSRP1-modulated apoptosis process and its knockdown increased the sensitivity of HCC cells to doxorubicin, 5-Fluorouracil, and cisplatin. We also identified microRNA-497 (miR-497) as a posttranscriptional regulator of SSRP1. Ectopic expression of miR-497 inhibited 3'-untranslated-region-coupled luciferase activity and suppressed endogenous SSRP1 expression at both messenger RNA and protein levels. For the first time, we proved that SSRP1 upregulation contributed to HCC development and the tumor-suppressive miR-497 served as its negative regulator.

[The effects and mechanism of islet amyloid polypeptide on insulin secretion in INS-1 cells stimulated by glibenclamide].

OBJECTIVE: To observe the effects, and study the mechanism of islet amyloid polypeptide (IAPP) on insulin secretion in INS-1 cells stimulated by glibenclamide. METHODS: Whole cell patch clamp technique was employed to study the influences of short exposure to IAPP on electrophysiological characteristics of ATP-sensitive K+ channel (K(ATP) channel) upon sulfonylurea stimulation. Intracellular free calcium changes in this process was observed by laser scanning confocal microscope. Insulin was measured by enzyme-linked immunoassay. RESULTS: (1) Insulin secretion stimulated by 1 micomol/L glibenclamide was significantly decreased from (11.43 +/- 1.22) microg/L to (9.40 +/- 0.87) microg/L and to (7.11 +/- 1.85) microg/L after 1 micromol/L and 10 micromol/L IAPP incubation, respectively. (2) Glibenclamide-stimulated calcium influx was dose dependently inhibited by IAPP from 1 micromol/L to 10 micromol/L, with the AUC of fluorescence intensity-time reduced from 427.78 +/- 2.32 to 380.59 +/- 1.49, and to 246.53 +/- 8.41, respectively. (3) Compared with that in control cells (14.59 +/- 0.69) mV, the half activation voltage of KA, channel in response to glibenclamide was significantly increased to (28.75 +/- 0.77) mV and to (46.95 +/- 1.81) mV in cells pretreated with 1 micromol/L and 10 micromol/L IAPP, implicating an inhibitory effect of IAPP on activation of K(ATP) channel. CONCLUSION: Short-term exposure to high concentration of IAPP inhibited glibenclamide-induced closure of K(ATP) channels and decreased calcium influx, which may ultimately lead to the reduction of insulin secretion in INS-1 cells

Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: a prospective randomized controlled trial.

BACKGROUND & AIMS: The purpose of this study was to evaluate whether use of combined radiofrequency ablation (RFA) and percutaneous iodine-125 ((125)I) seed implantation results in better progression-free survival compared with the use of RFA alone in patients with hepatocellular carcinoma. METHODS: 136 patients were randomly assigned to undergo HCC treatment with RFA and percutaneous iodine-125 seed implantation (RFA-(125)I, n=68) or RFA-only (n=68). A total of 91 patients had hepatitis B viral infection in both groups. Rates of tumour recurrence and overall survival were evaluated. RESULTS: The probabilities of recurrence at 1-, 3-, and 5-years were 4.5%, 22.1%, and 39.8% in the RFA-(125)I group; and 14.8%, 35.3%, and 57.4% in the RFA-only group, respectively. The recurrence rate in the RFA-(125)I group was significantly lower than in the RFA-only group (HR, 0.508; 95% CI, 0.317-0.815; p=0.004 by log-rank test). Local and intrahepatic recurrence was significantly lower in the RFA-(125)I group than in the RFA-only group (7.3% vs. 22.0%, p=0.012 by log-rank test; 17.6% vs. 32.3%, p=0.041 by log-rank test). The probabilities of survival at 1-, 3-, and 5-years were 100%, 86.7%, and 66.1% in the RFA-(125)I group and 95.6%, 75.0%, and 47.0% in the RFA-only group, respectively. The survival rate in the RFA-(125)I group was significantly better than in the RFA-only group (HR, 0.502; 95% CI, 0.313-0.806; p=0.003 by log-rank test). Cox regression model indicated that the treatment group and tumour size were both recurrence-related and overall survival-related prognostic factors. CONCLUSIONS: There were significant differences in overall survival and cumulative recurrence between RFA-(125)I and RFA-only for patients with small HCCs (⩽3 cm). Treatment with RFA-(125)I facilitated better local and intrahepatic tumour control and long-term survival compared with treatment of RFA alone. ClinicalTrials.gov Identifier: NCT01717729.

Associations of four surrogate insulin resistance indexes with non-alcoholic steatohepatitis in Chinese patients with obesity: a cross-sectional study.

OBJECTIVES: This study was designed to evaluate the association of four surrogate indexes of IR with NASH in patients with obesity. METHODS: A total of 270 patients who underwent bariatric surgery, were included in this cross-sectional study. NASH was diagnosed based on liver biopsies. Binary logistics regression analyses were performed to assess the associations of four surrogate indexes of IR (HOMA-IR, Matsuda index, TyG, and TG/HDL-C) with NASH in patients with obesity. The restricted cubic spline was used to assess the dose-response associations of surrogate indexes of IR with NASH after adjusting for confounding factors. RESULTS: NASH was diagnosed in 136 patients, with a prevalence of 50.37%. Compared with tertile 1, the fully adjusted ORs (95% CIs) of NASH for tertile 3 were 2.711(1.113-6.608) and 0.297 (0.152-0.579) for TyG and Matsuda index. Consistently, per SD increment of TyG were still significantly associated with 64% increased risks of NASH, and per SD increment of Matsuda index were still significantly associated with 38% decreased risks of NASH. In contrast, no significant associations were found between HOMA-IR and TG/HDL-C and the risk of NASH in patients with obesity (all P > 0.05). After adjusting covariates in restricted cubic splines, the risk of NASH decreased with the increment of Matsuda Index levels (P-nonlinear = 0.442, P-overall = 0.007) and with the decrement of TyG levels (P-nonlinear = 0.004, P-overall = 0.001). CONCLUSIONS: In patients with obesity, TyG and Matsuda index were independently related to the risk of NASH after adjustment for traditional risk factors. In addition, compared with HOMA-IR and TG/HDL-C, the Matsuda index and TyG may be more suitable for NASH prediction in patients with obesity.

Predictive values of stress hyperglycaemia and glycosylated haemoglobin on admission for long-term recovery of cardiac function in patients with acute myocardial infarction after primary percutaneous coronary intervention.

We aimed to explore the predictive values of stress hyperglycaemia (SHG) and glycosylated haemoglobin (HbA1c) levels on admission for long-term recovery of cardiac function in patients with acute myocardial infarction (AMI) after primary percutaneous coronary intervention (PPCI). A total of 210 AMI patients were randomly selected. The levels of SHG and HbA1c were measured on admission, and all patients were treated with PPCI and followed up for one year. According to the recovery status of cardiac function during follow up, the patients were divided into a good recovery group and a poor recovery group. At one year after treatment, there were statistically significant differences in the levels of SHG (6.75 ± 0.69 vs 7.81 ± 0.92 mmol/l) and HbA1c (5.13 ± 0.25 vs 5.91 ± 0.39%) between the good and poor recovery groups (p < 0.05). The levels of SHG and HbA1c were associated with long-term recovery of cardiac function (p < 0.05). The receiver operating characteristic curves were plotted, and the area under the curves of SHG and HbA1c for predicting the long-term recovery of cardiac function were > 0.70. The levels of SHG and HbA1c were closely associated with longterm recovery of cardiac function after PPCI in AMI patients, displaying high predictive values.

Insulin Resistance, but Not Obstructive Sleep Apnea Is Associated with Hepatic Steatosis in Chinese Patients with Severe Obesity.

INTRODUCTION: Severe obesity is often present with non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA). Emerging researches suggest OSA plays an important role in NAFLD development and progression while the relationship between OSA and NAFLD is still conflicting. The interaction of OSA and NAFLD should be further evaluated as obesity surges. The purpose of this study was to assess the prevalence of OSA and NAFLD in patients with obesity undergoing bariatric surgery and evaluate the association between OSA and severity of NAFLD. METHODS: 141 patients with severe obesity undergoing preoperative polysomnography and intraoperative liver biopsy during bariatric surgery were investigated. Clinical, anthropometric variables, liver enzymes, fasting blood glucose, fasting serum insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. The severity of NAFLD was assessed by degree of steatosis, ballooning, intralobular inflammation, and NAFLD activity score. The diagnosis and severity assessment of OSA was based on an apnea/hypopnea index (AHI). RESULTS: OSA was diagnosed in 127 (90.07%), NAFLD in 124 (87.94%), and non-alcoholic steatohepatitis in 72 (51.06%) patients. There was a statistical difference in BMI, waist circumstance, neck circumstance, high-density lipoprotein cholesterol, fasting insulin, and HOMA-IR among the three groups divided by the severity of AHI. In addition, the distribution of hepatic steatosis grades among the three groups was statistically different (p = 0.025). AHI was significantly associated with HOMA-IR and hepatic steatosis when assessing the association between OSA parameters and liver histology in NAFLD (p < 0.05). Patients with steatosis of grades 1-3 had significantly elevated aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, triglycerides, fasting insulin, fasting glucose, HOMA-IR, and AHI compared with the patients with steatosis of grade 0. In a multivariable logistic analysis, the positive association between AHI and hepatic steatosis attenuated after adjusting for HOMA-IR. CONCLUSION: Prevalence of OSA and NAFLD was high in patients with obesity eligible for bariatric procedures. HOMA-IR, but not AHI, was an independent risk factor for hepatic steatosis in this population.

[Retracted] SIRT1 promotes tumorigenesis of hepatocellular carcinoma through PI3K/PTEN/AKT signaling.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the control ß­actin western blots shown in Figs. 1B and 6 were strikingly similar to data that had already appeared in a different form in the following publication: Lei Y, Liu H, Yang Y, Wang X, Ren N, Li B, Liu S, Cheng J, Fu X and Zhang J: Interaction of LHBs with C53 promotes hepatocyte mitotic entry: A novel mechanism for HBV­induced hepatocellular carcinoma. Oncol Rep 29: 151­159, 2012. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 28: 311­318, 2012; DOI: 10.3892/or.2012.1788].

Development, Validation, and Application of a Scoring Model for Non-alcoholic Steatohepatitis.

PURPOSE: The aim of this study was to explore risk factors of NASH and then develop a non-invasive scoring model in Chinese patients with obesity. A scoring system was then applied to assess the effect of sleeve gastrectomy on NASH. METHODS: A total of 243 patients with obesity were included and divided into NASH group and non-NASH group according to the pathological results of liver biopsy. Logistic regression was used to determine risk factors of NASH. A scoring model was derived by risk factors of NASH. Then, postoperative follow-up was performed in 70 patients. RESULTS: Among the 243 patients, 118 (48.56%) patients showed NASH. Multivariate logistic regression identified aspartate aminotransferase (AST) (>21.50 IU/L), high-density lipoprotein cholesterol (HDL-C) (<1.155mmol/L), and homeostasis model assessment (HOMA-IR) (>9.368) as independent risk factors of NASH. The model included above risk factors showed a negative predictive value (NPV) of 70.38% in the low-risk category and a positive predictive value (PPV) of 85.71% in the high-risk category, with the area under the receiver operator curve (AUROC) of 0.737. Bariatric surgery resulted in a sharp decline in AST and HOMA-IR and a significant increase of HDL-C. The points of scoring model were improved at 6 months after surgery. CONCLUSION: A non-invasive scoring model was derived by the risk factors of NASH included AST, HDL-C, and HOMA-IR and applied to the postoperative follow-up. After sleeve gastrectomy, the above risk factors and points of scoring model were significantly improved.

Strengthened Decellularized Porcine Valves via Polyvinyl Alcohol as a Template Improving Processability.

The heart valve is crucial for the human body, which directly affects the efficiency of blood transport and the normal functioning of all organs. Generally, decellularization is one method of tissue-engineered heart valve (TEHV), which can deteriorate the mechanical properties and eliminate allograft immunogenicity. In this study, removable polyvinyl alcohol (PVA) is used to encapsulate decellularized porcine heart valves (DHVs) as a dynamic template to improve the processability of DHVs, such as suturing. Mechanical tests show that the strength and elastic modulus of DHVs treated with different concentrations of PVA significantly improve. Without the PVA layer, the valve would shift during suture puncture and not achieve the desired suture result. The in vitro results indicate that decellularized valves treated with PVA can sustain the adhesion and growth of human umbilical vein endothelial cells (HUVECs). All results above show that the DHVs treated with water-soluble PVA have good mechanical properties and cytocompatibility to ensure post-treatment. On this basis, the improved processability of DHV treated with PVA enables a new paradigm for the manufacturing of scaffolds, making it easy to apply.

[Corrigendum] Crocetin induces apoptosis of BGC­823 human gastric cancer cells.

Following the publication of the above article, an interested reader drew to the authors' attention that Fig. 2 (showing morphological characteristics of cultured BGC­823 cells as visualized by microscopic analysis) and Fig. 3 (showing crocetin­induced apoptosis of the BGC­823 cells) on p. 523 appeared to feature panels containing overlapping data. The authors re­examined their original data, and realized that inadvertent errors were made during the compilation of these figures; specifically, the data shown in Fig. 2C (for the the 5­µM docetaxel group) and Fig. 3D (for the DMSO group) were selected incorrectly. The corrected versions of Figs. 2 and 3 are shown below and on the next page, now featuring the correct data for Figs. 2C and 3D. All the authors agree with the publication of this corrigendum, and are grateful of the Editor of Molecular Medicine Reports for granting them the opportunity to publish this. Furthermore, they regret that these errors were introduced into the paper, even though they did not substantially alter any of the major conclusions reported in the paper, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 9: 521­526, 2014; DOI: 10.3892/mmr.2013.1851].

RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer.

RNF43 is a tumor suppressor for various cancers and is considered to drive carcinogenesis when mutated. However, the correlation between RNF43 mutation and colorectal cancer (CRC) immunotherapy remains unreported. We evaluated the role of RNF43 using publicly available data from the Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). In addition, further analysis was performed on an internal validation cohort (hcohort). The mutant profiles of RNF43 were analyzed in 873 Chinese CRC patients. The relationship between clinical pathologic features and RNF43 were analyzed using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics were associated with overall survival using Cox regression and the Kaplan-Meier method. We found that RNF43 mutation was significantly associated with high TMB and high MSI score (all p-values < 0.05) in the MSKCC cohort. Additionally, RNF43 mutation was found to be enriched in MSI instability. Kaplan-Meier survival analysis revealed that patients with RNF43 mutation had better OS compared to RNF43 wild-type (not reached vs. 13 months, HR, 0.12; 95% CI 0.03 to 0.49; P = 0.0034). However, no association was observed between RNF43 and OS in the TCGA cohort (HR, 1.83; 95% CI 0.66 to 5.07; P = 0.2479). Our CRC hcohort confirmed the significance of RNF43 mutation in predicting better clinical outcomes, including ORR (45% vs. 21%, P = 0.0468). RNF43 mutation correlated with a high tumor mutation burden (P < 0.001). The mutation frequency of RNF43 in CRC patients was 8.4% (73/873); RNF43 G659Vfs*41 was found to be the most frequent mutation site. In patients with RNF43 mutations, TP53, KRAS, and TGFBR2 were genes with a high frequency of mutations. Compared with RNF43 wild-type patients, those with RNF43 mutations had a higher TMB score and a greater proportion of MSI-H, but no difference in PD-L1 expression. Moreover, the content of immune-related B cells, CD8+ T cells, neutrophils, and dendritic cells was higher in the RNF43 mutant group than in the wild-type group. Our results suggest that RNF43 mutation may correlate with better OS in CRC patients receiving PD-1/PD-L1 inhibitors. The exact mechanisms underlying RNF43 require further investigation.

Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction.

Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI.

Low Serum Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate Are Associated With Coronary Heart Disease in Men With Type 2 Diabetes Mellitus.

Aims: Sex hormones play an important role in the pathogenesis of cardiovascular disease (CVD). This cross-sectional study aimed to explore the associations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with coronary heart disease (CHD) and stroke in middle-aged and elderly patients with type 2 diabetes mellitus (T2DM). Materials and Methods: A total of 995 patients with T2DM were included in the study analysis. Serum levels of DHEA and DHEAS were quantified using liquid chromatography-tandem mass spectrometry. Binary logistic regression analyses were performed to assess the associations of DHEA and DHEAS with CHD and stroke. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal DHEA and DHEAS cutoff values for the detection of CHD in men with T2DM. Results: In men with T2DM, after adjustment for potential confounders in model 3, the risk of CHD decreased with an increasing serum DHEA level [odds ratio (OR) = 0.38, quartile 4 vs. quartile 1; 95% confidence interval (CI) = 0.16-0.90; p = 0.037 for trend). Consistently, when considered as a continuous variable, this association remained significant in the fully adjusted model (OR = 0.59, 95% CI = 0.40-0.87, p < 0.05). When taken as a continuous variable in model 3, serum DHEAS level was also inversely related to the risk of CHD among men (OR = 0.56, 95% CI = 0.38-0.82, p < 0.05). Similarly, this relationship remained statistically significant when DHEAS was categorized into quartiles (OR = 0.27, quartile 4 vs. quartile 1; 95% CI = 0.11-0.67; p = 0.018 for trend). ROC curve analyses revealed that the optimal cutoff values to detect CHD in men with T2DM were 6.43 nmol/L for DHEA and 3.54 µmol/L for DHEAS. In contrast, no significant associations were found between DHEA and DHEAS on the one hand and stroke on the other in men and women with T2DM (all p > 0.05). Conclusions: Serum DHEA and DHEAS were significantly and negatively associated with CHD in middle-aged and elderly men with T2DM. This study suggests potential roles of DHEA and DHEAS in CHD pathogenesis.

MiR-132-3p inhibits proliferation, invasion and migration of colorectal cancer cells via down-regulating FOXP2 expression.

OBJECTIVE: colorectal cancer (CRC) is a common cancer with high mortality. This study aimed to investigate the role of microRNA (miR)-132-3p on proliferation, invasion and migration of CRC cells. MATERIALS AND METHODS: qRT-PCR and Western blot analyses were used to determine the expression of miR-132-3p and forking box (FOX) protein 2 (FOXP2) in CRC cell line CACO-2. The expression of miR-132-3p and FOX was regulated using miR inhibitor and siRNA, and the viability and migration ability of the transfected cells were assessed. Cell cycle dependent kinase (CDK) 1, cyclin D1, matrix metalloproteinase (MMP)-2 and MMP-9 were detected using Western blots. The dual luciferase reporter gene assays were used to verify the targeting of miR-132-3p to FOXP2. RESULTS: Compared with control cells, FOXP2 and miR-132-3p expressions were decreased or increased significantly (P<0.05), respectively in CACO-2 cells. Up-regulation of miR-132-3p effectively inhibited the proliferation, migration and invasion of CACO-2 cells, and suppressed the expression of FORX2, cyclin-dependent kinase 1 (CDK1), cyclin D1, MMP-2 and MMP-9. Luciferase reporter gene assays reveled that FOXP2 expression was negatively regulated by miR-132-3p. Knockdown of FOXP2 using siRNA significantly reduced the proliferation and migration of CACO-2 cells, down-regulated the expression FOXP2 as well as CDK1, cyclin D1, MMP-2 and MMP-9. Since FOXP2 is targeted by miR-132-3p, it is likely that miR-132-3p-mediated reduction of proliferation and migration of CACO-2 cells was achieved via reduced translation of FOXP2 mRNA. CONCLUSIONS: miR-132-3p inhibits the proliferation, migration and invasion of CRC cells. This is likely achieved via negative regulation of the targeted FOXP2 expression. This role may be further explored for therapeutic applications in CRC.

Low Serum Dehydroepiandrosterone Is Associated With Diabetic Kidney Disease in Men With Type 2 Diabetes Mellitus.

Background: The associations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with diabetic kidney disease (DKD) remained unclear. Thus, this cross-sectional study aimed to explore the associations of DHEA and DHEAS with the risk of DKD in patients with T2DM. Methods: The information of 1251 patients with T2DM were included in this study. Serum DHEA and DHEAS were quantified using liquid chromatography-tandem mass spectrometry assays. Multivariate logistic regression analyses were used to assess the associations of DHEA and DHEAS with DKD as well as high urine albumin to creatinine ratio (ACR). Results: In men with T2DM, the risk of DKD decreased with an increasing DHEA concentration after adjustment for traditional risk factors; the fully adjusted OR (95% CI) for tertile3 vs tertile1 was 0.37 (0.19-0.70; P = 0.010 for trend). Similarly, when taking high ACR as the outcome, low DHEA levels were still significantly associated with increased odds of high ACR (OR, 0.37; 95% CI, 0.19-0.72 for tertile3 vs tertile1; P = 0.012 for trend). The restricted cubic spline showed that the risk of DKD gradually decreased with the increment of serum DHEA levels (P-overall = 0.007; P-nonlinear = 0.161). DHEAS was not independently associated with the risk of DKD in men. In contrast, no significant relationships were found between DHEA and DHEAS and the risk of DKD in women (all P > 0.05). Conclusions: In men with T2DM, low serum DHEA levels were independently related to the risk of DKD after adjustment for traditional risk factors. Our finding highlights the potential role of DHEA in the development of DKD in men with T2DM.