Statistical Analysis of Stress Signals from Bridge Monitoring by FBG System.

In this paper, a fiber Bragg grating (FBG)-based stress monitoring system instrumented on an orthotropic steel deck arch bridge is demonstrated. The FBG sensors are installed at two types of critical fatigue-prone welded joints to measure the strain and temperature signals. A total of 64 FBG sensors are deployed around the rib-to-deck and rib-to-diagram areas at the mid-span and quarter-span of the investigated orthotropic steel bridge. The local stress behaviors caused by the highway loading and temperature effect during the construction and operation periods are presented with the aid of a wavelet multi-resolution analysis approach. In addition, the multi-modal characteristic of the rainflow counted stress spectrum is modeled by the method of finite mixture distribution together with a genetic algorithm (GA)-based parameter estimation approach. The optimal probability distribution of the stress spectrum is determined by use of Bayesian information criterion (BIC). Furthermore, the hot spot stress of the welded joint is calculated by an extrapolation method recommended in the specification of International Institute of Welding (IIW). The stochastic characteristic of stress concentration factor (SCF) of the concerned welded joint is addressed. The proposed FBG-based stress monitoring system and probabilistic stress evaluation methods can provide an effective tool for structural monitoring and condition assessment of orthotropic steel bridges.

Population pharmacokinetics and safety of eptifibatide in healthy Chinese volunteers and simulations on the dose regimens approved for a Western population.

OBJECTIVE: This study was designed to evaluate the pharmacokinetics (PK) and safety of eptifibatide in healthy Chinese volunteers and provide information for the further study in the Chinese population. METHODS: 30 healthy volunteers (15 male) were enrolled in the study and divided into three dose groups (45 µg x kg⁻¹, 90 µg x kg⁻¹, and 180 µg x kg⁻¹). Plasma and urine samples were drawn after one single-bolus administration and measured by LC-MS/MS. The plasma and urine data were analyzed simultaneously by the population approach using the NONMEM software and evaluated by the visual predicted check (VPC) and bootstraping. The PK profiles of dose regimens approved for a Western population in the Chinese population were simulated. RESULTS: A two-compartment model adequately described the PK profiles of eptifibatide. The clearance (CL) and the distribution volume (V1) of the central compartment were 0.128 L x h⁻¹ x kg⁻¹ and 0.175 L x kg⁻¹, respectively. The clearance (Q) and V2of the peripheral compartment were 0.0988 L x h⁻¹ x kg⁻¹ and 0.147 L x kg⁻¹, respectively. The elimination fraction from plasma to urine (F0) was 17.2%. No covariates were found to have a significant effect. Inter-individual variabilites were all within 33.9%. The VPC plots and bootstrap results indicated good precision and prediction of the model. The simulations of the approved regimens in the Chinese population showed much lower steady-state concentrations than the target concentration obtained from the Western clinical trials. No severe safety events were found in this study. CONCLUSIONS: The PK model of eptifibatide was established and could provide PK information for further studies in the Chinese population.

[Determination of Six Ingredients in Gardenia jaminoides Fruits with Quantitative Analysis of Muti-components by Single Marker].

OBJECTIVE: To establish a method of quantitative analysis of multi-components, by single marker(QAMS)for simultaneously determining six ingredients in Gardenia jasminoides fruits. METHODS: A multi-wavelength segmentation detection method was used. A methodological mode was found to analysis six ingredients in Gardenia jasminoides fruits by quantitative analysis of QAMS. Taken geniposide as reference to create RCF with gardenia acid, chlorogenic acid, crocin I, crocin II and crocin III. RESULTS: The good reproducibility and acceptable durability of method was validated between two HPLC systems and three columns. 20 batches of Gardenia jaminoides fruits was analysis, and the results showed good linear correlation compared to external standard method (r > 0. 999). CONCLUSION: QAMS can be used as quality evaluation method of multi-component Gardenia jaminoides fruits.

Population pharmacokinetic/pharmacodynamic model of clozapine for characterizing the relationship between accumulated exposure and PANSS scores in patients with schizophrenia.

BACKGROUND: The aim of this study was to characterize the relationship between accumulated exposure of clozapine and changes in Positive and Negative Syndrome Scale (PANSS) score in Chinese patients with schizophrenia by pharmacokinetic/pharmacodynamic (PK/PD) modeling. METHODS: Sparse clozapine PK data and PANSS scores were collected from 2 clinical studies of Chinese inpatients with schizophrenia. Two other rich PK data sets were included for more accurate assessment of clozapine PK characteristics. The relationship between clozapine-accumulated exposure and PANSS score was investigated using linear, log-linear, E(max), and sigmoid models, and each model was evaluated using visual predictive condition and normalized prediction distribution error methods. Simulations based on the final PK/PD model were preformed to investigate the effect of clozapine on PANSS scores under different dose regimens. RESULTS: A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy volunteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis. A first-order 2-compartment PK model with covariates gender and smoking status influencing systemic clearance adequately described the PK profile of clozapine. The decrease in total PANSS score during treatment was best characterized using cumulated clozapine area under the curve (AUC) data in the E(max) model. The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4%, and the cumulated AUC(50) (cAUC(50)) required to attain half of E(max) was 296 mg·L(-1)·h(-1)·d(-1). The simulations demonstrated that the accelerated dose titration and constant dose regimens achieved a similar maximum drug response but with a slower relief of symptoms in dose titration regimen. CONCLUSIONS: The PK/PD model can describe the clinical response as measured by decreasing PANSS score during treatment and may be useful for optimizing the dose regimen for individual patients.

Single-cell transcriptomics reveals ferrimagnetic vortex iron oxide nanoring-mediated mild magnetic hyperthermia exerts antitumor effects by alleviating macrophage suppression in breast cancer.

The potential of Ferrimagnetic vortex iron oxide nanoring-mediated mild magnetic hyperthermia (FVIO-MHT) in solid tumor therapy has been demonstrated. However, the impact of FVIO-MHT on the tumor microenvironment (TME) remains unclear. This study utilized single-cell transcriptome sequencing to examine the alterations in the TME in response to FVIO-MHT in breast cancer. The results revealed the cellular composition within the tumor microenvironment (TME) was primarily modified due to a decrease in tumor cells and an increased infiltration of myeloid cells. Subsequently, an enhancement in active oxygen (ROS) metabolism was observed, indicating oxidative damage to tumor cells. Interestingly, FVIO-MHT reprogrammed the macrophages' phenotypes, as evidenced by alterations in the transcriptome characteristics associated with both classic and alternative activated phenotypes. And an elevated level of ROS generation and oxidative phosphorylation suggested that activated phagocytosis and inflammation occurred in macrophages. Additionally, cell-cell communication analysis revealed that FVIO-MHT attenuated the suppression between tumor cells and macrophages by inhibiting phagocytic checkpoint and macrophage migration inhibitory factor signaling pathways. Inhibition of B2m, an anti-phagocytosis checkpoint, could promote macrophage-mediated phagocytosis and significantly inhibit tumor growth. These data emphasize FVIO-MHT may promote the antitumor capabilities of macrophages by alleviating the suppression between tumor cells and macrophages.

Identification of ASF1A and HJURP by global H3-H4 histone chaperone analysis as a prognostic two-gene model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis. Abnormal expression of H3-H4 histone chaperones has been identified in many cancers and holds promise as a biomarker for diagnosis and prognosis. However, systemic analysis of H3-H4 histone chaperones in HCC is still lacking. Here, we investigated the expression of 19 known H3-H4 histone chaperones in HCC. Integrated analysis of multiple public databases indicated that these chaperones are highly expressed in HCC tumor tissues, which was further verified by immunohistochemistry (IHC) staining in offline samples. Additionally, survival analysis suggested that HCC patients with upregulated H3-H4 histone chaperones have poor prognosis. Using LASSO and Cox regression, we constructed a two-gene model (ASF1A, HJURP) that accurately predicts prognosis in ICGC-LIRI and GEO HCC data, which was further validated in HCC tissue microarrays with follow-up information. GSEA revealed that HCCs in the high-risk group were associated with enhanced cell cycle progression and DNA replication. Intriguingly, HCCs in the high-risk group exhibited increased immune infiltration and sensitivity to immune checkpoint therapy (ICT). In summary, H3-H4 histone chaperones play a critical role in HCC progression, and the two-gene (ASF1A, HJURP) risk model is effective for predicting survival outcomes and sensitivity to immunotherapy for HCC patients.

FANCI Inhibition Induces PARP1 Redistribution to Enhance the Efficacy of PARP Inhibitors in Breast Cancer.

Breast cancer is a global public health concern with high mortality rates, necessitating the development of innovative treatment strategies. PARP inhibitors have shown efficacy in certain patient populations, but their application is largely limited to cancers with homologous recombination deficiency. Here, we identified the suppression of FANCI as a therapeutic strategy to enhance the efficacy of PARP inhibitors in breast cancer. Elevated FANCI expression in breast cancer was associated with poor prognosis and increased cell proliferation and migration. FANCI interacted with PARP1, and suppressing FANCI limited the nuclear localization and functionality of PARP1. Importantly, FANCI inhibition sensitized breast cancer cells to the PARP inhibitor talazoparib in the absence of BRCA mutations. Additionally, the CDK4/6 inhibitor palbociclib enhanced the sensitivity of breast cancer cells to talazoparib through FANCI inhibition. These findings highlight the potential of targeting FANCI to enhance the efficacy of PARP inhibitors in treating breast cancer.

Population pharmacokinetics of blonanserin in Chinese healthy volunteers and the effect of the food intake.

OBJECTIVE: The aim of the study was to better understand blonanserin population pharmacokinetic (PK) characteristics in Chinese healthy subjects. METHODS: Data from two studies with 50 subjects were analyzed to investigate the population PK characteristics of blonanserin at single dose (4, 8, and 12 mg) under fasting, multidose (4 mg bid or 8 mg qd for 7 days) and under food intake condition (single dose, 8 mg). Blonanserin plasma concentrations were detected using the high performance liquid chromatography tandem mass spectrometry (LC/MS/MS). A nonlinear mixed-effects model was developed to describe the blonanserin concentration-time profiles. RESULTS: A two compartment model with first-order absorption was built to describe the time-course of blonanserin. The population-predicted system apparent clearance (CL/F), volume of apparent distribution in center (V(1)/F), and the first-order absorption rate constant (Ka) of blonanserin under fasting was 1230 L/h, 9500 L, and 3.02 h(-1), respectively. Food intake decreased Ka of blonanserin to 0.78 h(-1). The relative bioavailability between fasting and food intake estimated by the final model was 55%. No clinically significant safety issues were identified. CONCLUSION: This is the first study assessing the PK profile of blonanserin with population PKs method. The results can be used for simulation in further clinical trial and optimize individual dosage regimens using a Bayesian methodology in patients.

Cloning and characterization of a cDNA coding 3-hydroxy-3-methylglutary CoA reductase involved in glycyrrhizic acid biosynthesis in Glycyrrhiza uralensis.

The roots of Glycyrrhiza uralensis are widely used in Chinese medicine for their action of clearing heat, detoxicating, relieving cough, dispelling sputum and tonifying spleen and stomach. The reason why Glycyrrhiza uralensis has potent and significant actions is that it contains various active secondary metabolites, especially glycyrrhizic acid. In the present study, we cloned the cDNA coding 3-hydroxy-3-methylglutary CoA reductase (HMGR) involved in glycyrrhizic acid biosynthesis in Glycyrrhiza uralensis. The corresponding cDNA was expressed in Escherichia coli as fusion proteins. Recombinant HMGR exhibited catalysis activity in reduction of HMG-CoA to mevalonic acid (MVA) just as HMGR isolated from other species. Because HMGR gene is very important in the biosynthesis of glycyrrhizic acid in Glycyrrhiza uralensis, this work is significant for further studies concerned with strengthening the efficacy of Glycyrrhiza uralensis by means of increasing glycyrrhizic acid content and exploring the biosynthesis of glycyrrhizic acid in vitro.

A novel influenza A (H1N1) vaccine in various age groups.

BACKGROUND: There is an urgent need for a vaccine that is effective against the 2009 pandemic influenza A (H1N1) virus. METHODS: A split-virus, inactivated candidate vaccine against the 2009 H1N1 virus was manufactured, and we evaluated its safety and immunogenicity in a randomized clinical trial. Subjects were between 3 and 77 years of age, stratified into four age groups. The immunization schedule consisted of two vaccinations, 21 days apart. Subjects were injected with placebo or with vaccine, with or without alum adjuvant, at doses of 7.5 microg, 15 microg, or 30 microg. Serologic analysis was performed at baseline and on days 21 and 35. RESULTS: A total of 2200 subjects received one dose, and 2103 (95.6%) received the second dose, of vaccine or placebo. No severe adverse side effects associated with the vaccine were noted. In the nonadjuvanted-vaccine groups, injection-site or systemic reactions, most mild in nature, were noted in 5.5 to 15.9% of subjects. Among the subjects receiving 15 microg of nonadjuvanted vaccine, a hemagglutination-inhibition titer of 1:40 or more was achieved by day 21 in 74.5% of subjects between 3 and 11 years of age, 97.1% of subjects between 12 and 17 years, 97.1% of subjects between 18 and 60 years, and 79.1% of subjects 61 years of age or older; by day 35, the titer had been achieved in 98.1%, 100%, 97.1%, and 93.3% of subjects, respectively. The proportion with a titer of 1:40 or more was generally highest among the subjects receiving 30 microg of vaccine, with or without adjuvant. Vaccine without adjuvant was associated with fewer local reactions and greater immune responses than was vaccine with adjuvant. CONCLUSIONS: These data suggest that a single dose of 15 microg of hemagglutinin antigen without alum adjuvant induces a typically protective immune response in the majority of subjects between 12 and 60 years of age. Lesser immune responses were seen after a single dose of vaccine in younger and older subjects. (ClinicalTrials.gov number, NCT00975572).

Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia.

AIM: To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters. METHODS: Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors. RESULTS: A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients. CONCLUSION: Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.

rs144012689 is a highly specific representative marker of HLA-B*15:02 in the Chinese population.

Objective: To develop an accurate and rapid real-time PCR technique for HLA-B*15:02 genotyping and investigate HLA-B*15:02 allele frequency in four ethnic populations in China. Materials & methods: Based on the highly specific representative markers, a real-time PCR assay was developed for HLA-B*15:02 genotyping, and HLA-B*15:02 allele frequencies were screened in four ethnic populations of China. Sequence-based typing was used to validate the accuracy of the assay. Results: The sensitivity and specificity of the assay were 100%, and the detection limit was 0.2 ng. The frequency of HLA-B*15:02 alleles distributed in the Bouyei population was significantly higher than in the Han group (p < 0.01). Neither the Tibetan nor the Uyghur population carried the HLA-B*15:02 haplotype. Conclusion: The authors developed an accurate HLA-B*15:02 genotyping method for evaluating the risk of adverse drug reactions induced by carbamazepine in various ethnic populations in China.

Biomedical Indicators of Patients with Non-Puerperal Mastitis: A Retrospective Study.

BACKGROUND: Non-puerperal mastitis (NPM), a recurrent chronic inflammation of non-lactating breast, often proves tremendous difficulty in treatment, and it may give rise to its complicated symptoms and unclear etiology. Furthermore, the clinical morbidity rate of NPM has been increasing in recent years. METHODS: Overall, 284 patients diagnosed with NPM were consecutively recruited as cases in this study, and patients with benign breast disease (n = 1128) were enrolled as control. The clinical, biomedical, and pathological indicators were analyzed. Univariate and multivariate logistic analysis were used to distinguish risks between NPM and benign breast mass patients. Furthermore, according to the pathological characteristics, the patients of NPM were classified into two subgroups: mammary duct ectasia (MDE) and granulomatous lobular mastitis (GLM). The differences of biomedical indicators between MDE and GLM groups were also analyzed. RESULTS: Compared with benign breast mass group, the level of high-density lipoprotein (HDL-C) significantly decreased, while lipoprotein(a) (Lp(a)) and blood glucose (GLU) both increased in NPM group. According to univariate and multivariate logistic analysis, the onset age and HDL-C were generally decreased, while Lp(a) and GLU were increased in NPM group. The onset age, HDL-C, Lp(a), and GLU were modeled to distinguish NPM and benign breast mass. Significant differences were also observed between MDE and GLM patients in biomedical indicators, such as lipoprotein(a) (Lp(a)), lactate dehydrogenase (LDH), creatine kinase (CK), total cholesterol (TC), and so on. CONCLUSIONS: Our results indicated for the first time that biomarkers were associated with NPM. The biomedical indicators involved in lipid metabolism might be important factors in the development and treatment of NPM. In addition, MDE and GLM are two diseases with different inflammatory states of NPM. These findings would be helpful for a better understanding of NPM and give us some insights to develop new diagnostic and therapeutic strategies.

Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients.

Paroxetine is one of the most potent selective serotonin reuptake inhibitors (SSRIs) approved for treating depression, panic disorder, and obsessive-compulsive disorder. There is evidence linking genetic polymorphisms and nonlinear metabolism to the Paroxetine's pharmacokinetic (PK) variability. The purpose of the present study was to develop a population PK (PPK) model of paroxetine in Chinese patients, which was used to define the paroxetine's PK parameters and quantify the effect of clinical and baseline demographic factors on these PK characteristics. The study included 184 inpatients with psychosis (103 females and 81 males), with a total of 372 serum concentrations of paroxetine for PPK analyses. The total daily dosage ranged from 20 to 75 mg. One compartment model could fit the PKs characterize of paroxetine. Covariate analysis revealed that dose, formulation, and sex had a significant effect on the PK parameters of paroxetine; however, there was no evident genetic influence of CYP2D6 enzymes on paroxetine concentrations in Chinese patients. The study determined that the population's apparent distribution volume (V/F) and apparent clearance (CL/F), respectively, were 8850 and 21.2 L/h. The CL/F decreased 1-2-fold for each 10 mg dose increase, whereas the different formulations caused a decrease in V/F of 66.6%. Sex was found to affect bioavailability (F), which decreased F by 47.5%. Females had higher F values than males. This PPK model described data from patients with psychosis who received paroxetine immediate-release tablets (IR-T) and/or sustained-release tablets (SR-T). Paroxetine trough concentrations and relative bioavailability were different between formulations and sex. The altered serum concentrations of paroxetine resulting from individual variants and additive effects need to be considered, to optimize the dosage regimen for individual patients.

[Comparison study of model evaluation methods: normalized prediction distribution errors vs. visual predictive check].

The objective of this study is to compare the normalized prediction distribution errors (NPDE) and the visual predictive check (VPC) on model evaluation under different study designs. In this study, simulation method was utilized to investigate the capability of NPDE and VPC to evaluate the models. Data from the false models were generated by biased parameter typical value or inaccurate parameter inter-individual variability after single or multiple doses with the same sampling time or multiple doses with varied sampling time, respectively. The results showed that there was no clear statistic test for VPC and it was difficult to make sense of VPC under the multiple doses with varied sampling time. However, there were corresponding statistic tests for NPDE and the factor of study design did not affect NPDE significantly. It suggested that the clinical data and model which VPC was not fit for could be evaluated by NPDE.

Diverging targets mediate the pathological roleof miR-199a-5p and miR-199a-3p by promoting cardiac hypertrophy and fibrosis.

MicroRNA-199a-5p (miR-199a-5p) and -3p are enriched in the myocardium, but it is unknown whether miR-199a-5p and -3p are co-expressed in cardiac remodeling and what roles they have in cardiac hypertrophy and fibrosis. We show that miR-199a-5p and -3p are co-upregulated in the mouse and human myocardium with cardiac remodeling and in Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs). miR-199a-5p and -3p could aggravate cardiac hypertrophy and fibrosis in vivo and in vitro. PPAR gamma coactivator 1 alpha (Ppargc1a) and sirtuin 1 (Sirt1) were identified as target genes to mediate miR-199a-5p in promoting both cardiac hypertrophy and fibrosis. However, miR-199a-3p aggravated cardiac hypertrophy and fibrosis through targeting RB transcriptional corepressor 1 (Rb1) and Smad1, respectively. Serum response factor and nuclear factor κB p65 participated in the upregulation of miR-199a-5p and -3p in Ang-II-treated NMVCs and mouse CFs, and could be conversely elevated by miR-199a-5p and -3p. Together, Ppargc1a and Sirt1, Rb1 and Smad1 mediated the pathological effect of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively. This study suggests a possible new strategy for cardiac remodeling therapy by inhibiting miR-199a-5p and -3p.

Oncogenic action of the exosome cofactor RBM7 by stabilization of CDK1 mRNA in breast cancer.

RNA exosome can target the specific RNAs for their processing/degradation by distinct exosome cofactors. As a key component in exosome cofactors, RNA binding motif protein 7 (RBM7) shows the binding specificity for uridine-rich sequences in mRNAs via its RNA recognition motifs. However, the specific function of RBM7 in human breast cancer remains unclear. In vitro, experiments revealed that knockdown of RBM7 dramatically inhibited breast cancer cell proliferation, while inducing G1 cell cycle arrest; the opposite was true when RBM7 was overexpressed. Meanwhile, experiments in vivo confirmed the oncogenic function of RBM7 in breast cancer. RNA sequencing and the following pathway analysis found that cyclin-dependent kinase1 (CDK1) was one of the main gene regulated by RBM7. Overexpression of RBM7 increased CDK1 expression, while RBM7 knockdown decreased it. RIP assays additionally found that RBM7 bound directly to CDK1 mRNA. It was also showed that RBM7 could directly bind to the AU-rich elements (AREs) in 3'-UTR of CDK1 mRNA, which contributed to the stability of CDK1 mRNA by lengthening its half-life. More importantly, the oncogenic activity reduced by knockdown of RBM7 could be rescued by overexpression of CDK1 both in vitro and in vivo, but mutant CDK1 failed. All the evidences implied RBM7 promoted breast cancer cell proliferation by stabilizing CDK1 mRNA via binding to AREs in its 3'-UTR. As we knew, it was the first attempt to connect the RNA exosome to the tumor development, providing new insights into the mechanisms of RNA exosome-linked diseases.

Correction to: The RNA binding protein RBMS3 inhibits the metastasis of breast cancer by regulating Twist1 expression.

In the original publication of this article [1], the molecular weight of RBMS3 was incorrectly noted as 38 KDa within Fig 1A, Fig 2A and Fig 2B. The figures have been updated to list the correct molecular weight of RBMS3 as 41 KDa.

Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p binding to Gata4.

AIMS: Circular RNAs (circRNAs) are involved in gene regulation in a variety of physiological and pathological processes. The present study aimed to investigate the effect of circRNA_000203 on cardiac hypertrophy and the potential mechanisms involved. METHODS AND RESULTS: CircRNA_000203 was found to be up-regulated in the myocardium of Ang-II-infused mice and in the cytoplasma of Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Enforced expression of circRNA_000203 enhances cell size and expression of atrial natriuretic peptide and ß-myosin heavy chain in NMVCs. In vivo, heart function was impaired and cardiac hypertrophy was aggravated in Ang-II-infused myocardium-specific circRNA_000203 transgenic mice (Tg-circ203). Mechanistically, we found that circRNA_000203 could specifically sponge miR-26b-5p, -140-3p in NMVCs. Further, dual-luciferase reporter assay showed that miR-26b-5p, -140-3p could interact with 3'-UTRs of Gata4 gene, and circRNA_000203 could block the above interactions. In addition, Gata4 expression is transcriptionally inhibited by miR-26b-5p, -140-3p mimic in NMVCs but enhanced by over-expression of circRNA_000203 in vitro and in vivo. Functionally, miR-26b-5p, -140-3p, and Gata4 siRNA, could reverse the hypertrophic growth in Ang-II-induced NMVCs, as well as eliminate the pro-hypertrophic effect of circRNA_000203 in NMVCs. Furthermore, we demonstrated that NF-κB signalling mediates the up-regulation of circRNA_000203 in NMVCs exposed to Ang-II treatment. CONCLUSIONS: Our data demonstrated that circRNA_000203 exacerbates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p leading to enhanced Gata4 levels.

TCDD-Inducible Poly-ADP-Ribose Polymerase (TIPARP), A Novel Therapeutic Target Of Breast Cancer.

BACKGROUND: TIPARP (TCDD-inducible poly-ADP-ribose polymerase), a mono-ADP-ribosyltransferase and a transcriptional repressor of aryl hydrocarbon receptor (AHR), was one of the potential therapeutic targets for human cancers identified by CRISPR-Cas9 screens recently. Studies about TIPARP on cancers are scarce till now, most of which just focus on expressions, while the functions have not been widely reported yet. Moreover, the TIPARP prognostic significance and therapeutic value of breast cancer is also uncertain. METHODS: The present study was performed to comprehensively analyze the expression pattern, prognostic effect, potential therapeutic function of TIPARP in breast cancer by pooling all currently available databases online including Oncomine, UALCAN, bc-GenExMiner, Kaplan-Meier Plotter, COSMIC, UCSC Xena, STRING, DAVID and Comparative Toxicogenomics Database. Further, we also performed several cell biology experiments including RT-qPCR, Western blot and CCK-8 in cellular and clinical sample levels to confirm the conclusions from bioinformatics analysis. RESULTS: TIPARP was expressed lower in tumor tissues comparing with normal tissues. Meanwhile, several clinical parameters of breast cancer patients were correlated with TIPARP expression. Further, higher TIPARP expression was related to preferable survival. Moreover, the mutations and DNA methylation of TIPARP might contribute to TIPARP dysregulation in breast cancer. Interactors with TIPARP were significantly enriched in telomere maintenance, telomere organization and mainly participated in pathways in cancer. Finally, several common drugs including metformin were observed to up-regulate the expression of TIPARP. CONCLUSION: TIPARP might act as a preferable prognostic marker of breast cancer through multiple biological processes such as DNA methylation, mutation as well as pathway related to telomere and so on. TIPARP could be considered as a potential therapeutic target for breast cancer. However, large-scale and comprehensive research is needed to clarify our results.