Elevation of Metrnß and Its Association with Disease Activity in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an auto-immune disease, the pathogenesis of which remains to be fully addressed. Metrnß is a novel cytokine involved in the pathogenesis of inflammatory disease, but its regulatory roles in SLE are unclear. We aimed to comprehensively investigate the clinical value of Metrnß in SLE. A massive elevation of circulating Metrnß levels was observed in SLE, and patients with an active phase displayed higher Metrnß concentrations than those with inactive phases. Additionally, we found that Metrnß expression was positively correlated with clinical indicators of SLE. Longitudinal cytokine and chemokine profiles revealed a disturbed immune response in SLE, with high activity profiles displayed severe pathogenic inflammation, and a positive correlation of the serum Metrnß with CXCL9, IL10, IL18 and IL1RA was observed as well. Moreover, Metrnß expressions exhibited an inverse correlation with Treg and B10. Of note, a significant decrease of ILC2 was found in SLE, and there was a negative correlation of Metrnß with ILC2 as well. Further ROC analysis showed that the area under the curve (AUC) for Metrnß was 0.8250 (95% CI: 0.7379-0.9121), with a cutoff value of 1131 pg/mL to effectively distinguish SLE patients from healthy controls. Our study herein demonstrated for the first time that Metrnß values were increased and were immunologically correlated with SLE activity, which could be utilized as an alternative biomarker for the early identification and predicting of the immuno-response of SLE.

TRIM29 regulates the SETBP1/SET/PP2A axis via transcription factor VEZF1 to promote progression of ovarian cancer.

Ovarian cancer (OC) is a common gynecological malignant tumor that seriously endangers the health of women worldwide. Tripartite motif containing 29 (TRIM29) is a TRIM family member that is frequently overexpressed in OC. However, the specific role of TRIM29 in OC remains obscure. To investigate the underlying molecular mechanism, a global proteomics analysis identified SET binding protein 1 (SETBP1) as a crucial target of TRIM29. Subsequently, the SETBP1/SET/Protein phosphatase 2 (PP2A) axis was confirmed to be required for the recovery of cancer stem cell (CSC)-like phenotype suppressed by TRIM29 knockdown. Mechanistically, TRIM29 facilitated SETBP1 transcriptional activation via the VEZF1 transcription factor. More importantly, TRIM29 promoted VEZF1 mRNA translation by recruiting RNA binding protein BICC1 to its 3'UTR. The clinical significance was established by the association of TRIM29 and SETBP1 expression with clinicopathological features in OC samples. The SETBP1/SET/PP2A axis driven by TRIM29 via transcription factor VEZF1 is at least one of the primary mechanisms underlying TRIM29 maintenance of the CSC-like characteristics in OC.

ISG15 is downregulated by KLF12 and implicated in maintenance of cancer stem cell-like features in cisplatin-resistant ovarian cancer.

Drug resistance is often developed during clinical chemotherapy of ovarian cancers. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) is possibly dependent on tumour context to promote or suppress progression of various tumours. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) was decreased in cisplatin-resistant ovarian cancer cells. The current study identified that both ectopic wild type and nonISGylatable mutant ISG15 expression inhibited CSC-like phenotypes of cisplatin-resistant ovarian cancer cells. Moreover, ectopic ISG15 expression suppressed tumour formation in nude mice. In addition, ISG15 downregulation promoted CSC-like features of cisplatin-sensitive ovarian cancer cells. Furthermore, low ISG15 expression was associated with poor prognosis in patients with ovarian cancer. Transcriptional repressor Krüppel-like factor 12 (KLF12) downregulated ISG15 in cisplatin-resistant cells. Our data indicated that downregulating ISG15 expression, via weakening effect of KLF12, might be considered as new therapeutic strategy to inhibit CSC phenotypes in the treatment of cisplatin-resistant ovarian cancer.

TRIM29 alters bioenergetics of pancreatic cancer cells via cooperation of miR-2355-3p and DDX3X recruitment to AK4 transcript.

TRIM29 is dysregulated in pancreatic cancer and implicated in maintenance of stem-cell-like characters of pancreatic cancer cells. However, the exact mechanisms underlying oncogenic function of TRIM29 in pancreatic cancer cells remain largely unclarified. Using a global screening procedure, the current study found that adenylate kinase 4 (AK4) was profoundly reduced by TRIM29 knockdown. In addition, our data demonstrated that TRIM29 knockdown altered bioenergetics and suppressed proliferation and invasion of pancreatic cancer cells via downregulation of AK4 at the posttranscriptional level. The current study demonstrated that upregulation of microRNA-2355-3p (miR-2355-3p) upregulated AK4 expression via facilitating DDX3X recruitment to the AK4 transcript, and TRIM29 knockdown thereby destabilized the AK4 transcript via miR-2355-3p downregulation. Collectively, our study uncovers posttranscriptional stabilization of the AK4 transcript by miR-2355-3p interaction to facilitate DDX3X recruitment. Regulation of AK4 by TRIM29 via miR-2355-3p thereby provides additional information for further identification of attractive targets for therapy with pancreatic cancer.

m6A-YTHDF1-mediated TRIM29 upregulation facilitates the stem cell-like phenotype of cisplatin-resistant ovarian cancer cells.

Ovarian cancer is the deadliest gynaecologic malignancy, and the five-year survival rate of patients is less than 35% worldwide. Cancer stem cells (CSCs) are a population of cells with stem-like characteristics that are thought to cause chemoresistance and recurrence. TRIM29 is aberrantly expressed in various cancers and associated with cancer development and progression. Previous studies showed that the upregulation of TRIM29 expression in pancreatic cancer is related to stem-like characteristics. However, the role of TRIM29 in ovarian cancer is poorly understood. In this study, we found that TRIM29 expression was increased at the translational level in both the cisplatin-resistant ovarian cancer cells and clinical tissues. Increased TRIM29 expression was associated with a poor prognosis of patients with ovarian cancer. In addition, TRIM29 could enhance the CSC-like characteristics of the cisplatin-resistant ovarian cancer cells. Recruitment of YTHDF1 to m6A-modified TRIM29 was involved in promoting TRIM29 translation in the cisplatin-resistant ovarian cancer cells. Knockdown of YTHDF1 suppressed the CSC-like characteristics of the cisplatin-resistant ovarian cancer cells, which could be rescued by ectopic expression of TRIM29. This study suggests TRIM29 may act as an oncogene to promote the CSC-like features of cisplatin-resistant ovarian cancer in an m6A-YTHDF1-dependent manner. Due to the roles of TRIM29 and YTHDF1 in the promotion of CSC-like features, they may become potential therapeutic targets to combat the recurrence of ovarian cancer.

ISG15 suppresses translation of ABCC2 via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin resistant ovarian cancer cells.

Cisplatin-based chemotherapies have long been considered as a standard chemotherapy in ovarian cancer. However, cisplatin resistance restricts beneficial therapy for patients with ovarian cancer. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the post-translational modification of diverse proteins. In this work, we found that ISG15 was downregulated in cisplatin resistant tissues and cell lines of ovarian cancer. Functional studies demonstrated that overexpression of wild type (WT) ISG15, but not nonISGylatable (Mut) ISG15 increased cell responses to cisplatin in resistant ovarian cancer cells. Furthermore, we found that WT ISG15 decreased ABCC2 expression at the protein level. Importantly, overexpression of ABCC2 blocked sensitizing effect of ISG15 on cisplatin. In addition, we identified that hnRNPA2B1 was recruited to 5'UTR of ABCC2 mRNA and promoted its translation, which was blocked by ISG15. We further demonstrated that hnRNPA2B1 could be ISGylated, and ISGylation blocked its recruitment to ABCC2 mRNA, thereby suppressed translation of ABCC2. Altogether, our data support targeting ISG15 might be a potential therapeutic strategy for patients with cisplatin-resistant ovarian cancer.

Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation.

TRIM family proteins are defined as E3 ubiquitin ligases because of their RING-finger domains. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the posttranslational modification of diverse proteins. Both TRIM29 and ISG15 play both pro-tumoral and anti-tumoral functions in cancer cells derived from different histology. In the current study, we demonstrated that correlation expression of TRIM29 and ISG15 in pancreatic ductal adenocarcinomas (PDACs). The current study demonstrated that TRIM29 knockdown destabilized ISG15 protein via promoting its processing by calpain 3 (CAPN3). Importantly, the current study found that TRIM29 knockdown suppressed cancer stem cell-like features of PDACs, which can be rescued by ISG15 independent of its conjugation function. In addition, the current study demonstrated that extracellular free ISG15 played an important role in maintenance of cancer stem cell-like features of PDACs. Thereby, the current study displayed a novel mechanism by which TRIM29 modulates ISG15 stability via CAPN3-mediated processing, and subsequently extracellular ISG15 maintains the cancer stem cell-like features of PDAC via autocrine mode of action.

The relationship between baseline exhaled nitric oxide levels and acute mountain sickness.

BACKGROUND: Acute mountain sickness (AMS) is a common disabling condition observed in people ascending to high altitudes. However, a simple predictive test for AMS is not known. The aim of this study was to assess the relationship between baseline exhaled nitric oxide (FENO) and AMS occurrence. METHODS: Eighty healthy lowland Chinese adults were recruited for this study. FENO was measured at baseline, as well as 6 and 24 hours after arrival in Tibet. The standard Lake Louise Score (LLS) consensus symptoms questionnaire was used to assess the incidence and severity of AMS. RESULTS: Individuals with a high LLS (> 3) had higher FENO levels at baseline and after arrival in Tibet than people with a low LLS (≤ 3) (baseline: 22.9 ± 11.9 versus 16.7 ± 6.4; 6 hours: 26.2 ± 16.7 versus 17.9 ± 5.7; 24 hours: 24.9 ± 13.1 versus 16.3 ± 1.7; all P < 0.01). Evaluation of risk factors revealed that female gender, diabetes and not smoking were associated with a high AMS score (all P < 0.05), but that hypertension showed no association (P > 0.05). CONCLUSIONS: This prospective observational study suggests that baseline FENO levels may be positively correlated with AMS in healthy Chinese lowlanders.

Fractional exhaled nitric oxide in healthy Tibetans at high altitude.

BACKGROUND: Fractional exhaled NO (FENO) is a marker of airway inflammation. For successful use of this marker it is important to have reference ranges from different healthy populations. The aim of this study was to establish these in healthy Tibetan adults who had always lived at high altitude on the Qinghai-Tibet Plateau. MATERIAL AND METHODS: The study included 145 healthy Tibetan subjects, aged 18 to 75 years, who were non-smokers. FENO was measured at a flow rate of 50 mL/s using a chemiluminescence analyzer. Residential altitude was classified as: Grade 1 (3678-3800 m), Grade 2 (3800-4200 m), or Grade 3 (>4200 m). Correlations between subject characteristics (age, sex, height, and weight), altitude, and FENO were investigated. RESULTS: The geometric mean FENO (95% CI) was 15.4 (7.0, 35.0) parts per billion (ppb). The 95% upper limit of the log-transformed data was 33.0 ppb, which was slightly lower than that for Han Chinese, and much lower than in the Northwest Han population. Mean FENO values were higher in males (16.8 ppb) than females (14.3 ppb) and inversely related to altitude. Multiple linear regression analysis showed that FENO was predicted by the equation Ln (FENO)=[2.844+0.161 × sex (1 for male; 0 for female) -0.111 × altitude grade]. The residual standard deviation (SD) was 0.048, and the explanatory value was 7%. CONCLUSIONS: The upper limit of FENO in healthy Tibetan adults is 33 ppb. This value can be predicted on the basis of sex and altitude.

Association between heme oxygenase 1 gene promoter polymorphisms and susceptibility to coronary artery disease: a HuGE review and meta-analysis.

We performed a systematic review and meta-analysis of heme oxygenase 1 gene (HO-1) promoter polymorphisms and susceptibility to coronary artery disease (CAD) based on eligible studies retrieved from electronic databases from 2002 to 2013. Eleven studies, involving 10,170 patients with CAD and 6,868 controls, were included. Overall, no significantly decreased risk of CAD was found in persons with the SS genotype of the HO-1 (GT)n repeat length polymorphism compared with those with the LL + SL genotype. However, decreased risks of CAD were observed in the Asian subgroup, the coronary-artery-narrowing ≥50% subgroup, the myocardial infarction subgroup, the age- and sex-matched subgroup, and the good-quality-reports subgroup. The primary heterogeneity in the studies came from age and sex matching and the extent of coronary stenosis. CAD risk was significantly decreased for persons with the AA genotype of the T(-413)A single-nucleotide polymorphism versus those with the TT genotype, but most of the studies showed that the allele distribution was inconsistent with Hardy-Weinberg equilibrium. In this meta-analysis, we found that the (GT)n SS genotype was associated with decreased risk of CAD after controlling for biases due to age and sex matching, extent of coronary stenosis, ethnicity, and study quality. The relationship between the T(-413)A single-nucleotide polymorphism and CAD should be interpreted more cautiously.

Correlation between major adverse cardiac events and coronary plaque characteristics.

BACKGROUND: Unstable plaque is believed to be responsible for major adverse cardiac events (MACE). OBJECTIVE: To determine whether coronary computed tomography angiography (CCTA) could be used to predict future MACE. METHODS: Patients undergoing CCTA between January 2008 and February 2010 were consecutively enrolled in the study. The hospital database was screened for patients who later developed acute ST segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) or cardiac death. Plaque scores were calculated and analyzed using one-way ANOVA to examine the relationship between plaque scores and MACE. RESULTS: Of the 8557 patients who underwent CCTA, 1055 had hospital records available for follow-up. During follow-up, 25 patients experienced MACE including death (six patients), heart failure (two patients), STEMI (11 patients) and NSTEMI (six patients). The plaque scores were significantly increased in patients who later died, developed heart failure or experienced STEMI (P<0.05). Calcification, erosion and severe stenosis were responsible for the events (P<0.05). Mild and moderate lesions, positive remodelling, drug-eluting stent placement, occlusion and diffuse lesions were not predictive of MACE (P>0.05). CONCLUSION: Severe calcification, erosion and severe stenosis predict death, heart failure and STEMI.

Application of a new three-dimensional method for the measurement of coronary stent angulation and comparison with conventional methods.

The precision of the measurement of the angulation of coronary stents or lesions using coronary angiography (CA) and computed tomographic angiography (CTA) has not been established, and obtaining a rotating artery tree to measure angulation based on CTA is time-consuming. The aim of this study was to evaluate the utility of a new three-dimensional centerline method that we have developed for the measurement of coronary stent angulation based on CTA and to compare it with other conventional methods. We used the centerline method compacted by means of our new software, the conventional artery rotation method based on CTA and the simple CA method to measure the angulations of phantoms in vitro and stents implanted in patients. The precision and repetition of this new method was compared with those of the other two methods. The angulation values obtained from both the centerline and artery rotation methods based on CTA had high correlation and agreement with the true angulation values measured using a phantom; the 95 % confidence intervals (CIs) for the differences were -0.67° to 0.91° and -0.59° to 2.93°, respectively, while the difference between the value determined using the CA method and the true angulation of the phantoms ranged from 3° to 21.8° (median 8.1°). In clinical coronary stent measurement, the difference between artery rotation and centerline measurement was small (95 % CI -9.0° to 7.6°), and both methods had good repeatability. The time required to complete the measurement was considerably shorter (p < 0.001) using the centerline method than artery rotation method (12.5 ± 1.86 vs. 71.8 ± 13.6 s), while the CA method had poor precision and repeatability in the measurement of clinical stent angulation relative to the methods based on CTA (95 % CI -14.7° to 21.7°). Our three-dimensional centerline method based on CTA for the measurement of angulation was reliable and easy to implement in both clinical and basic research image analysis, and the centerline and conventional artery rotation methods can be used interchangeably. In addition, the value obtained for the coronary stent angulation using the CA method had a large bias.

[Coronary plaques identified by coronary computed tomography angiography and the risk factors for major adverse cardiac events: a correlation analysis].

OBJECTIVE: To investigate the correlation between the findings by coronary computed tomography angiography (CCTA) and the risk factors for major adverse cardiac events (MACE). METHODS: This cohort study involved 706 out-patients who received examination with CCTA between June, 2008 and April, 2011. The severity of coronary artery disease (CAD) was graded to normal, mild, moderate, severe, and revascularization. Pearson correlation analysis and ANOVA were used to evaluate the relationship between the risk factors for CAD and coronary plaques identified by CCTA, and the predictive accuracy was determined by the receiver-operating characteristic (ROC) curve. RESULTS: Of the 706 patients, 58.63% were found to have abnormal CCTA findings. A older age, hypertension, hyperlipidemia, diabetes mellitus, cerebral infarction, CAD, and myocardial infarction were associated with an significantly increased incidence of coronary plaques (P<0.01). The Framingham score, LDL, HCY, IMT, HDL and TC were also significantly correlated with the severity of the coronary plaques (P<0.05). The ROC curves showed that Framingham risk score (0.845), Cr (0.766), HCY (0.697), IMT (0.693) and HDL (0.316) had greater predictive value for the occurrence of coronary plaques (P<0.001). CONCLUSION: The Framingham risk score, Cr, HCY, IMT and HDL are validated by CCTA as the major coronary risk factors and can be used for screening of CAD.

[The effect of telomerase reverse transcriptase on 5-HT induced pulmonary artery smooth muscle cells proliferation].

OBJECTIVE: To investigate the effect of telomerase reverse transcriptase (TERT) to the proliferation of 5-HT induced pulmonary artery smooth muscle cells (PASMCs). METHODS: The PASMCs proliferation experiment was performed to detect the effort on PASMCs of 5-HT or ASODN TERT (antisense oligoribonucleotides TERT designed according to the rat TERT mRNA sequence of gene bank). The immunohistochemistry staining experiment and the in situ hybridization experiment were to detect the TERT protein and mRNA expression with 5-HT or ASODN TERT. FITC marked ASODN TERT experiment was done to research the distribution of ASODN TERT in PASMCs. RESULTS: 5-HT promoted PASMCs proliferation in a dose-dependent manner (10(-9) - 10(-5) mol/L). 5-HT also significantly increased TERT expression at protein and mRNA levels as shown by immunohistochemistry staining and the in situ hybridization studies. This effect could be blocked by ASODN TERT in a time and dose-dependent manner. CONCLUSIONS: Our experiments show TERT is one of the key factors in the procession of 5-HT induced PASMCs proliferation. ASODN TERT might be a potential therapy agent for pulmonary hypertension.