A long non-coding RNA-based signature predicts early recurrence in hepatocellular carcinoma.

BACKGROUND: Early recurrence is the main obstacle for long-term survival of hepatocellular carcinoma (HCC) patients after curative resection. OBJECTIVE: We aimed to develop a long non-coding RNA (lncRNA) based signature to predict early recurrence. METHODS: Using bioinformatics analysis and quantitative reverse transcription PCR (RT-qPCR), we screened for lncRNA candidates that were abnormally expressed in HCC. The expression levels of candidate lncRNAs were analyzed in HCC tissues from 160 patients who underwent curative resection, and a risk model for the prediction of recurrence within 1 year (early recurrence) of HCC patients was constructed with linear support vector machine (SVM). RESULTS: An lncRNA-based classifier (Clnc), which contained nine differentially expressed lncRNAs including AF339810, AK026286, BC020899, HEIH, HULC, MALAT1, PVT1, uc003fpg, and ZFAS1 was constructed. In the test set, this classifier reliably predicted early recurrence (AUC, 0.675; sensitivity, 72.0%; specificity, 63.1%) with an odds ratio of 4.390 (95% CI, 2.120-9.090). Clnc showed higher accuracy than traditional clinical features, including tumor size, portal vein tumor thrombus (PVTT) in predicting early recurrence (AUC, 0.675 vs 0.523 vs 0.541), and had much higher sensitivity than Barcelona Clinical Liver Cancer (BCLC; 72.0% vs 50.0%), albeit their AUCs were comparable (0.675 vs 0.678). Moreover, combining Clnc with BCLC significantly increased the AUC, compared with Clnc or BCLC alone in predicting early recurrence (all P< 0.05). Finally, logistic and Cox regression analyses suggested that Clnc was an independent prognostic factor and associated with the early recurrence and recurrence-free survival of HCC patients after resection, respectively (all P= 0.001). CONCLUSIONS: Our lncRNA-based classifier Clnc can predict early recurrence of patients undergoing surgical resection of HCC.

The Impact of Smoking, Sex, Infection, and Comedication Administration on Oral Olanzapine: A Population Pharmacokinetic Model in Chinese Psychiatric Patients.

BACKGROUND AND OBJECTIVE: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting. METHODS: A total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate. RESULTS: Typical estimates for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h-1, 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model's performance was good, stable, and precise. CONCLUSION: This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.

This study included a total of 1546 serum olanzapine concentrations from 354 Chinese adult psychiatric patients that were analyzed by a complex mathematical model. The goal was to explore how oral olanzapine is eliminated from the body in Chinese psychiatric patients and how to personalize its dosing. Prior studies using similar complex mathematical models only studied the effects of sex and smoking on olanzapine elimination. This study also investigated the influence of co-occurrence of infection and comedications, including dangguilonghui tablets. This is a Chinese herbal medicine used to treat constipation, including constipation secondary to olanzapine treatment. Olanzapine elimination was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine elimination was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. This study contributes to the improvement of oral olanzapine dosing personalization, but further studies are needed to verify the effects of infection and comedications, including valproate and dangguilonghui.

Quantitative determination of risperidone, paliperidone and olanzapine in human serum by liquid chromatography-tandem mass spectrometry coupled with on-line solid-phase extraction.

A recent guideline recommends therapeutic drug monitoring for risperidone, paliperidone and olanzapine, which are frequently used second-generation antipsychotics. We developed a simple high-performance liquid chromatography-tandem mass spectrometry coupled with an online solid-phase extraction method that can be used to measure risperidone, paliperidone and olanzapine using small (40 µL) samples. The analytes were extracted from serum samples automatically pre-concentrated and purified by C8 (5 µm, 2.1 × 30 mm) solid-phase extraction cartridges, then chromatographed on an Xbidge™ C18 column (3.5 µm, 100 × 2.1 mm) thermostatted at 30°C with a mobile phase consisting of 70% acetonitrile and 30% ammonium hydroxide 1% solution at an isocratic flow rate of 0.3 mL/min, and detected with tandem mass spectrometry. The assay was validated in the concentration range from 2.5 to 160 ng/mL. Intra- and inter-day precision for all analytes was between 1.1 and 8.2%; method accuracy was between 6.6 and 7.6%. The risperidone and paliperidone assay was compared with a high-performance liquid chromatography-ultraviolet assay currently used in our hospital for risperidone and paliperidone therapeutic drug monitoring, and the results of weighted Deming regression analysis showed good agreement. For the olanzapine assay, we compared 20 samples in separate re-assays on different days; all the relative errors were within the 20% recommended limit.

An Interface for Biomedical Big Data Processing on the Tianhe-2 Supercomputer.

Big data, cloud computing, and high-performance computing (HPC) are at the verge of convergence. Cloud computing is already playing an active part in big data processing with the help of big data frameworks like Hadoop and Spark. The recent upsurge of high-performance computing in China provides extra possibilities and capacity to address the challenges associated with big data. In this paper, we propose Orion-a big data interface on the Tianhe-2 supercomputer-to enable big data applications to run on Tianhe-2 via a single command or a shell script. Orion supports multiple users, and each user can launch multiple tasks. It minimizes the effort needed to initiate big data applications on the Tianhe-2 supercomputer via automated configuration. Orion follows the "allocate-when-needed" paradigm, and it avoids the idle occupation of computational resources. We tested the utility and performance of Orion using a big genomic dataset and achieved a satisfactory performance on Tianhe-2 with very few modifications to existing applications that were implemented in Hadoop/Spark. In summary, Orion provides a practical and economical interface for big data processing on Tianhe-2.

Identification of Potent Chloride Intracellular Channel Protein 1 Inhibitors from Traditional Chinese Medicine through Structure-Based Virtual Screening and Molecular Dynamics Analysis.

Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score. Then, 30 potent hits were achieved from the top 500 TCM compounds using cluster and ligand-protein interaction analysis. Finally, MD simulation was employed to validate the stability of interactions between each hit and CLIC1 protein from docking simulation, and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) analysis was used to refine the virtual hits. Six TCM compounds with top MM-GBSA scores and ideal-binding models were confirmed as the final hits. Our study provides information about the interaction between TCM compounds and CLIC1 protein, which may be helpful for further experimental investigations. In addition, the top 6 natural products structural scaffolds could serve as building blocks in designing drug-like molecules for CLIC1 inhibition.

Therapeutic drug monitoring of psychotropic drugs in China: a nationwide survey.

OBJECTIVE: To understand the status of therapeutic drug monitoring (TDM) of psychotropic drugs in psychiatric facilities in mainland China and to lay the foundation for improvement of TDM in psychiatry. METHODS: A cross-sectional survey was conducted with a locally developed questionnaire among psychiatric facilities in which TDM of psychotropic drugs was available. The questionnaire included laboratory situations, implementation of TDM, equipment and analytical methods, internal quality control (IQC), and external quality assessment (EQA). RESULTS: Forty-seven of the 58 delivered questionnaires were collected from the psychiatric facilities involving 26 provinces in mainland China. The response rate was 81.0%. Among all facilities surveyed, lithium was the most common psychotropic drug (68.1% of the laboratories) monitored by TDM, followed by clozapine (44.7%), carbamazepine (25.5%), chlorpromazine (21.3%), norclozapine (19.1%), risperidone (19.1%), paliperidone (17.0%), valproic acid (14.9%), and quetiapine (10.6%). Only 10.2% of the laboratories had recommendations for dose adjustments based on their TDM reports. Others only provided drug concentration results with no clinical recommendations. The analytical methods used included high-performance liquid chromatography, liquid chromatography with tandem mass spectrometric detection, and immunoassay. For lithium, most hospitals used ion-selective electrode methods. IQC and EQA were still in their infancy. CONCLUSIONS: This first nationwide survey showed that TDM has been available in a considerable number of psychiatric hospitals across China. Though current equipment and analytical methods meet the TDM need, much improvement is needed, particularly in new analytical method development, interpretation of results, consultation services, and quality control, including IQC and EQA. Guidance or consensus guideline for TDM of psychotropic drugs in the Chinese language is also urgently required.

Determination of atomoxetine in human plasma by a high performance liquid chromatographic method with ultraviolet detection using liquid-liquid extraction.

A HPLC method with UV detection (210 nm) was developed and validated for the quantification of atomoxetine, a new medication for the treatment of attention deficit/hyperactivity disorder, in human plasma. Following a two-step liquid-liquid extraction with diethyl ether, the analyte and internal standard (maprotiline) were separated using an isocratic mobile phase of acetonitrile/phosphate buffer (39/61, v/v, pH 6.6) on a reverse phase Inertsil C(18) column. Linearity was verified over the range of 3.12-200 ng/mL atomoxetine in plasma. The lowest limit of detection is 2.5 ng/mL (S/N=10). This HPLC method was validated with within- and between-batch precisions of 4.9-14.4% and 4.7-13.1%, respectively. The within- and between-batch biases were -1.9 to 1.4% and 0.1-13.8%, respectively. Commonly used psychotropic drugs and frequently coadministered drugs did not interfere with the drug and internal standard. This method is simple, economical and specific, and has been used successfully in a pharmacokinetic study of atomoxetine.