Radiomic Prediction of CCND1 Expression Levels and Prognosis in Low-grade Glioma Based on Magnetic Resonance Imaging.

OJECTIVES: Low-grade glioma (LGG) is associated with increased mortality owing to recrudescence and the tendency for malignant transformation. Therefore, it is imperative to discover novel prognostic biomarkers as existing traditional prognostic biomarkers of glioma, including clinicopathological features and imaging examinations, are unable to meet the clinical demand for precision medicine. Accordingly, we aimed to evaluate the prognostic value of cyclin D1 (CCND1) expression levels and construct radiomic models to predict these levels in patients with LGG MATERIALS AND METHODS: A total of 412 LGG cases from The Cancer Genome Atlas (TCGA) were used for gene-based prognostic analysis. Using magnetic resonance imaging (MRI) images stored in The Cancer Imaging Archive with genomic data from TCGA, 149 cases were selected for radiomics feature extraction and model construction. After feature extraction, the radiomic signature was constructed using logistic regression (LR) and support vector machine (SVM) analyses. RESULTS: CCND1 was identified as a prognosis-related gene with differential expression in tumor and normal samples and plays a role in regulating both the cell cycle and immune response. Landmark analysis revealed that high-expression levels of CCND1 were beneficial for survival (P < 0.05) in advanced LGG. Four optimal radiomics features were selected to construct radiomics models. The performance of LR and SVM achieved areas under the curve of 0.703 and 0.705, as well as 0.724 and 0.726 in the training and validation sets, respectively. CONCLUSION: Elevated levels of CCND1 expression could impact the prognosis of patients with LGG. MRI-based radiomics, especially the AUC values, can serve as a novel tool for predicting CCND1 expression and understanding the correlation between elevated CCND1 expression and prognosis. AVAILABILITY OF DATA AND MATERIALS: The datasets analyzed during the current study are available in the TCGA, TCIA, UCSC XENA and GTEx repository, https://portal.gdc.cancer.gov/, https://www.cancerimagingarchive.net/, https://xenabrowser.net/datapages/, https://www.gtexportal.org/home/.

Six mitophagy-related hub genes as peripheral blood biomarkers of Alzheimer's disease and their immune cell infiltration correlation.

Background: Alzheimer's disease (AD), a neurodegenerative disorder with progressive symptoms, seriously endangers human health worldwide. AD diagnosis and treatment are challenging, but molecular biomarkers show diagnostic potential. This study aimed to investigate AD biomarkers in the peripheral blood. Method: Utilizing three microarray datasets, we systematically analyzed the differences in expression and predictive value of mitophagy-related hub genes (MRHGs) in the peripheral blood mononuclear cells of patients with AD to identify potential diagnostic biomarkers. Subsequently, a protein-protein interaction network was constructed to identify hub genes, and functional enrichment analyses were performed. Using consistent clustering analysis, AD subtypes with significant differences were determined. Finally, infiltration patterns of immune cells in AD subtypes and the relationship between MRHGs and immune cells were investigated by two algorithms, CIBERSORT and single-sample gene set enrichment analysis (ssGSEA). Results: Our study identified 53 AD- and mitophagy-related differentially expressed genes and six MRHGs, which may be potential biomarkers for diagnosing AD. Functional analysis revealed that six MRHGs significantly affected biologically relevant functions and signaling pathways such as IL-4 Signaling Pathway, RUNX3 Regulates Notch Signaling Pathway, IL-1 and Megakaryocytes in Obesity Pathway, and Overview of Leukocyteintrinsic Hippo Pathway. Furthermore, CIBERSORT and ssGSEA algorithms were used for all AD samples to analyze the abundance of infiltrating immune cells in the two disease subtypes. The results showed that these subtypes were significantly related to immune cell types such as activated mast cells, regulatory T cells, M0 macrophages, and neutrophils. Moreover, specific MRHGs were significantly correlated with immune cell levels. Conclusion: Our findings suggest that MRHGs may contribute to the development and prognosis of AD. The six identified MRHGs could be used as valuable diagnostic biomarkers for further research on AD. This study may provide new promising diagnostic and therapeutic targets in the peripheral blood of patients with AD.

Developing a competing risk nomogram that predicts the survival of patients with a primary hepatic neuroendocrine tumor.

Primary hepatic neuroendocrine tumor (PHNET) is rare liver cancer and related prognostic factors are unclear. The aim of this study was to analyze the prognostic risk factors of patients with PHNETs and establish an assessment model for prognosis. The clinical information of 539 patients with PHNETs who met the criteria for inclusion was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. These patients were randomly assigned to the training (269 cases) and validation sets (270 cases). Prognostic factors in patients with PHNETs were screened using the Cox proportional regression model and Fine-Gray competing risk model. Based on the training set analysis using the Fine-Gray competing risk model, a nomogram was constructed to predict cumulative probabilities for PHNET-specific death. The performance of the nomogram was measured by using receiver operating characteristic curves, the concordance index (C-index), calibration curves, and decision curve analysis (DCA). No differences in clinical baseline characteristics between the training and validation sets were observed, and the Fine-Gray analysis showed that surgery and more than one primary malignancy were associated with a low cumulative probability of PHNET-specific death. The training set nomograms were well-calibrated and had good discriminative ability, and good agreement between predicted and observed survival was observed. Patients with PHNETs with a high-risk score had a significantly increased risk of PHNET-specific death and non-PHNET death. Surgical treatment and the number of primary malignancies were found to be independent protective factors for PHNETs. The competing risk nomogram has high accuracy in predicting disease-specific survival (DSS) for patients with PHNETs, which may help clinicians to develop individualized treatment strategies.

Integrated analysis and identification of hub genes as novel biomarkers for Alzheimer's disease.

Alzheimer's disease (AD) is an intractable and progressive neurodegenerative disorder that can lead to severe cognitive decline, impaired speech, short-term memory loss, and finally an inability to function in daily life. For patients, their families, and even all of society, AD can impart great emotional pressure and economic costs. Therefore, this study aimed to investigate potential diagnostic biomarkers of AD. Using the Gene Expression Omnibus (GEO) database, the expression profiles of genes were extracted from the GSE5281, GSE28146, and GSE48350 microarray datasets. Then, immune-related genes were identified by the intersections of differentially expressed genes (DEGs). Functional enrichment analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Disease Ontology (DO), and Gene Set Enrichment Analysis (GSEA), were performed. Subsequently, random forest models and least absolute shrinkage and selection operator regression were used to further screen hub genes, which were then validated using receiver operating characteristic (ROC) curve analysis. Finally, 153 total immune-related DEGs were identified in relation to AD. DO analysis of these immune-related DEGs showed that they were enriched in "lung disease," "reproductive system disease," and "atherosclerosis." Single GSEA of hub genes showed that they were particularly enriched in "oxidative phosphorylation." ROC analysis of AGAP3 yielded an area under the ROC curve of 0.878 for GSE5281, 0.727 for GSE28146, and 0.635 for GSE48350. Moreover, immune infiltration analysis demonstrated that AGAP3 was related to follicular helper T cells, naïve CD4 T cells, naïve B cells, memory B cells, macrophages M0, macrophages M1, macrophages M2, resting natural killer (NK) cells, activated NK cells, monocytes, neutrophils, eosinophils, and activated mast cells. These results indicate that identifying immune-related DEGs might enhance the current understanding of the development and prognosis of AD. Furthermore, AGAP3 not only plays a vital role in AD progression and diagnosis but could also serve as a valuable target for further research on AD.

Sequential P-GEMOX and radiotherapy for early-stage extranodal natural killer/T-cell lymphoma: A multicenter study.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease. Combined modality therapy (CMT), namely chemotherapy combined with radiotherapy, has been recommended for patients with early-stage ENKTL. However, the optimal CMT has not been fully clarified. This study reports the efficacy and toxicity of sequential P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) and radiotherapy in a large Chinese cohort comprising of 202 patients diagnosed with early-stage ENKTL from six medical centers. The observed best overall response rate was 96.0% and 168 (83.2%) patients achieved complete remission. With a median follow-up of 44.1 months, the 3-year progression-free survival (PFS) and overall survival (OS) were 74.6% and 85.2%, respectively. Multivariate analysis suggested that extensive primary tumor (PFS, hazard ratio [HR] 3.660, 95% CI 1.820-7.359, p < 0.001; OS, HR 3.825, 95% CI 1.442-10.148, p = 0.007) and Eastern Cooperative Oncology Group performance status ≥ 2 (PFS, 3.042, 95% CI 1.468-6.306, p = 0.003; OS, HR 3.983, 95% CI 1.678-9.457, p = 0.02) were independent prognostic factors for survival outcomes. Among the established prognostic models for ENKTL, the nomogram-revised risk index model had optimal prognostic risk stratification ability (PFS, p < 0.001; OS, p < 0.001) and relatively balanced population distribution. The adverse events of this CMT were well-tolerated and manageable. In conclusion, sequential P-GEMOX and radiotherapy showed favorable efficacy with acceptable toxicity, and could be an effective treatment option for early-stage ENKTL patients.

Pharmacokinetic and tissue distribution study of ZCY-15, a novel compound against Alzheimer's disease, in rats by liquid chromatography-tandem mass spectrometry.

ZCY-15, N-(3,5-dimethyladamatan-1-yl)-N-(3-methylphenyl) urea, is a candidate compound synthesized from the memantine structure and has been shown to be remarkably effective in treating Alzheimer's disease. To elucidate the pharmacokinetics and tissue distribution of ZCY-15 in rats after oral and intravenous administration, a rapid and selective LC-MS/MS method was established for the determination of ZCY-15 in rat plasma and tissues. According to the dissolution characteristics, the plasma samples were prepared by acetonitrile protein precipitation and carbamazepine was selected as the internal standard (IS). After separation by gradient elution using Aqela Venusil ASB C8 (2.1 × 50 mm, 3 µm), the pretreated samples were analyzed in MRM mode in positive ESI mode. The effective detection limit of this method was 1.95-1000 ng·mL-1. Tissue samples were collected from the heart, liver, spleen, lung, kidney, fat, muscle, brain, hippocampus, testicles or ovaries, large intestine, small intestine and stomach. The proposed method demonstrated fine precision and accuracy for analyzing ZCY-15 in selected tissues within the concentration range of standard liquid chromatography-tandem mass spectrometry. The whole analysis time was 3.6 min per sample. After oral administration, the blood and tissue concentrations of ZCY-15 in female rats were significantly higher than those in male rats. The clearance rate of ZCY-15 in female rats was lower than that in male rats. The results confirmed that there were gender differences. It has been shown that ZCY-15 could pass through the blood-brain barrier and was highly concentrated in the hippocampus. We established the first bioanalytical method to quantify ZCY-15 in rodent bio-samples for ongoing pharmacokinetic and tissue distribution studies, and the results were expected to lay foundation for the subsequent studies.

[Analysis of the Predictive Value of EZH2 Expression Level on the Clinical Efficacy and Long-term Prognosis of Patients with Primary Gastrointestinal Diffuse Large B-cell Lymphoma].

OBJECTIVE: To investigate the predictive value of methyltransferase EZH2 expression level on the clinical efficacy and long-term prognosis of patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL). METHODS: 161 patients with newly treated PGI-DLBCL in our hospital from August 2013 to July 2019 were selected. The expression level of EZH2 protein was detected by immunohistochemistry, and the short-term efficacy and long-term survival differences of patients with different levels of EZH2 were compared. The predictive values of EZH2 expression level on the short-term efficacy and long-term prognosis of PGI-DLBCL patients were analyzed by Log-rank test and COX risk proportional regression model. Chi-square test and Logistic regression analysis were used to analyze the influencing factors of EZH2 expression level. RESULTS: The complete response (CR) and overal response(OR) rates of those with high EZH2 expression were significantly lower than those with low EZH2 expression (P<0.001). The median OS and PFS of EZH2 high-level and low-level expression group was 37, 31 months and 49, 42 months, respectively. The cumulative OS and PFS rates of the high-level expression group were significantly lower than those of the low-level expression group, and the differences were statistically significant (P<0.05). The high expression levels of H3K27me3, EZH2, BCL-2, BCL-6, c-MYC were closely related to the shortening of OS and PFS, while the high expression level of Ki-67 was closely related to the shortening of OS (P<0.05), of which the high expression levels of H3K27me3, EZH2, BCL-2, and BCL-6 were independent risk factors for shortening of OS and PFS. The expression level of EZH2 was positively correlated with the expression level of H3K27me3, BCL-6, c-MYC and Ki-67 (r=0.741, r=0.837, r=0.809, r=0.772), and the high expression levels of H3K27me3, BCL-6 and Ki-67 were independent factors influencing the high expression of EZH2. CONCLUSION: In patients with PGI-DLBCL, the high expression of EZH2 significantly reduces the short-term CR and OR rates, which is an independent risk factor for the shortening of long-term OS and PFS rates, and it is independently related to the high expression of H3K27me3 and BCL6.

The efficacy and toxicity of angiogenesis inhibitors for ovarian cancer: a meta-analysis of randomized controlled trials.

PURPOSE: To evaluate the efficacy and toxicity of angiogenesis inhibitors for the treatment of ovarian cancer patients, we conducted a meta-analysis of the published literature on this subject. METHODS: In this meta-analysis, we searched PubMed, EMBASE, Web of Science, and Cochrane Library databases for randomized controlled trials (RCTs). The literature search was performed up to August 12, 2019. The risk of bias of the included studies was evaluated using The Cochrane Collaboration's tool, and the statistical analyses were performed using RevMan 5.3 software. The sensitivity analysis was performed with Stata 12.0 software. RESULTS: 22 RCTs with 11,254 patients were included. Our meta-analysis demonstrates that angiogenesis inhibitors therapy can significantly improve progression-free survival (PFS) (hazard ratio [HR] 0.71, 95% CI 0.63-0.79, I2 = 80%, P < 0.00001) and overall survival (OS) (HR 0.95, 95% CI 0.90-0.99, I2 = 0%, P = 0.03) in ovarian cancer patients. The subgroups results suggest differences in the benefit in OS in first-line treatment (HR 1.00, 95% CI 0.93-1.08, I2 = 0%, P = 0.90) compared with treatment at relapse (HR 0.87, 95% CI 0.81-0.95, I2 = 0%, P = 0.0008). The PFS improved both in first-line treatment (HR 0.87, 95% CI 0.79-0.95, I2 = 60%, P = 0.003) and recurrent treatment (HR 0.60, 95% CI 0.53-0.67, I2 = 57% P < 0.0001) patients. The PFS and OS in recurrent group were prolonged both in the platinum-resistant group(PFS: HR 0.50, 95% CI 0.42-0.60, I2 = 0%, P < 0.00001; OS: HR 0.76, 95% CI 0.62-0.93, I2 = 0%, P = 0.007) and the platinum-sensitive group (PFS: HR 0.58, 95% CI 0.49-0.69, I2 = 64%, P < 0.00001; OS: HR 0.88, 95% CI 0.79-0.99, I2 = 0%, P = 0.03). However, this therapy is associated with a higher risk of common adverse events of grade ≥ 3 (risk ratio [RR]: 1.12; 95% CI 1.07-1.17; I2 = 0%, P = 0.68) such as arterial thromboembolic disease, ascites, diarrhea, gastrointestinal perforations, headache, hemorrhagic, hypertension, hypokalemia, leucopenia, pain, proteinuria, thrombocytopenia, and thrombosis or embolism. CONCLUSION: This meta-analysis suggests angiogenesis inhibitors may significantly improve PFS and OS of ovarian cancer patients and increase the incidence of common adverse events.

Efficacy and safety of urate-lowering treatments in patients with hyperuricemia: A comprehensive network meta-analysis of randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: Hyperuricemia (HUA) and gout are considerable public health problems because of their increasing incidence and interactions with other diseases. We aimed to evaluate the efficacy and safety of urate-lowering therapies (ULTs) for patients. METHODS: A systematic literature review was conducted, and a network meta-analysis was performed on the included studies using the Markov Chain Monte Carlo simulation method and a Bayesian statistical framework. We calculated surface under the cumulative ranking curve (SUCRA) values and performed clustered ranking to combine the efficacy and safety results. RESULTS: Twenty-two randomized controlled studies were identified for the efficacy analysis, and 20 studies were identified for the safety analysis. Compared with the placebo, the ULTs were efficient and safe. Febuxostat 120 mg/d and allopurinol 200 mg/d had the highest SUCRA scores for efficacy and safety, respectively. Clustered ranking results showed that febuxostat 120 mg/d was the best in terms of efficacy and safety, topiroxostat 120/160 mg/d was similar to febuxostat 80 mg/d in terms of efficacy but safer, and allopurinol was not inferior to topiroxostat. WHAT IS NEW AND CONCLUSION: Febuxostat had the best efficacy and safety results among the tested agents, and topiroxostat and allopurinol appeared to have fewer adverse events.

Upregulation of MYBL2 independently predicts a poorer prognosis in patients with clear cell renal cell carcinoma.

MYB protooncogene-like 2 (MYBL2) is a transcription factor that is upregulated and significantly associated with various human cancer types. However, the potential role of MYBL2 in clear cell renal cell carcinoma (ccRCC) is yet to be elucidated. Therefore, the expression and biological functions of MYBL2 in ccRCC were assessed in the current study using The Cancer Genome Atlas (TCGA). A Wilcoxon signed-rank test was performed to compare MYBL2 expression between ccRCC and normal tissues. Moreover, the association between MYBL2 expression and various clinicopathological factors was estimated using both the Wilcoxon signed-rank test and logistic regression. The differences in prognosis between patients with high- and low-MYBL2 expression were analyzed via the Kaplan-Meier method and Cox regression analysis. Finally, gene set enrichment analysis (GSEA) was performed to investigate the biofunctions of MYBL2 in ccRCC. It was revealed that MYBL2 was upregulated in ccRCC, and that the MYBL2 high-expression phenotype was significantly associated with sex, a high histological grade, an advanced clinical stage, tumor stage, lymph node metastasis, distant metastasis and poor overall survival (OS). It was also revealed, via the Cox regression analysis, that the upregulation of MYBL2 expression was able to independently predict a poor prognosis in patients with ccRCC. GSEA indicated that the intestinal immune network for IgA production, primary immunodeficiency, the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, the cytosolic DNA-sensing pathway, the p53 signaling pathway and the chemokine signaling pathway were all enriched in the high-MYBL2 expression datasets. In conclusion, the present findings indicate that MYBL2 may be used as an independent prognostic factor in patients with ccRCC.

A novel xanthine oxidase inhibitor WSJ-557 study on pharmacokinetics and tissue distribution in rats by UPLC-MS/MS.

As a novel non-purine xanthine oxidase inhibitor, WSJ-557 is a potential drug for gout. To determine the WSJ-557 concentration in plasma and various tissues of rats, a fast and sensitive method was first established by the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in this paper. The liquid-liquid extraction of ethyl acetate was adopted for the sample preparation, and carbamazepine was taken as the internal standard. In the process of chromatographic separation, MRM transitions for WSJ-557 and carbamazepine (internal standard, IS) were m/z 316.1 → 260.0 and m/z 237.0 → 194.0, correspondingly. The great linearity of WSJ-557 in all bio-samples was found in the corresponding concentration range (r > 0.99). The intra- and inter-day precision (RSD%) were below 9.5% in various tissues and plasma, whose accuracy (RE%) was within ±9.2%. This method was resoundingly employed to the WSJ-557 study on rat pharmacokinetics and tissue distribution after the intravenous administration and oral administration. The average absolute bioavailability (F) of WSJ-557 was 6.48%. The highest distribution level of gastric and intestinal tissues indicated that WSJ-557 was first absorbed in the stomach and intestine. Moreover, this analytical method provides a significant approach for the further development and investigation of WSJ-557.

Pharmacokinetics, bioavailability and tissue distribution study of JCC-02, a novel N-methyl-d-aspartate (NMDA) receptor inhibitor, in rats by LC-MS/MS.

JCC-02, N-(3,5-dimethyladamantan-1-yl)-N'-(3-chlorophenyl) urea, has been developed as a novel N-methyl-d-aspartate (NMDA) receptor inhibitor for the treatment of Alzheimer's disease (AD). In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to determine the concentration of JCC-02 in rat plasma and different tissues to investigate its pharmacokinetic behavior in vivo and distribution character in organs. The matrix samples were prepared by protein precipitation method with acetonitrile using gliclazide as the internal standard (IS). This validated method was successfully applied to JCC-02 pharmacokinetic study in rats after oral administration of low (0.7 mg·kg-1), medium (2 mg·kg-1) and high (6 mg·kg-1) concentration, intravenous administration (2 mg·kg-1) as well as tissue distribution in rats after administration of JCC-02 (2 mg·kg-1) orally. The results indicated that the area under the time curve (AUC0-∞) and peak plasma concentration (Cmax) were directly proportional to dosage and the pharmacokinetic behavior of JCC-02 in rats was a linear process with respect to dosage. JCC-02 could be absorbed into blood circulation rapidly because of its short time to reach peak plasma concentration (tmax). Meanwhile, JCC-02 has a low clearance and a high volume of distribution, which might result in its long half-time. Oral absolute bioavailability (F) of JCC-02 was (14.61 ±â€¯5.81)%, which was turned out to be low relatively. In tissues, the differences of JCC-02 concentration were quite large. After administration, small intestine (22.29 ±â€¯15.86 µg·mL-1), stomach (7.21 ±â€¯2.87 µg·mL-1), large intestine (1.27 ±â€¯0.57 µg·mL-1), liver (0.96 ±â€¯0.52 µg·mL-1) and fat (0.48 ±â€¯0.24 µg·mL-1) were the first five organs with the largest drug concentration. Small intestine could be the main part of drug absorption where most of the drug was distributed after oral administration. More importantly, JCC-02 could cross the blood-brain barrier (BBB), which may probably have a pretty good therapeutic effect on AD.

[Clinicopathological Features and Prognostic Factors of DLBCL].

OBJECTIVE: To analyze the clinicopathological features and prognostic factors of patients with diffuse large B-cell lymphoma(DLBCL). METHODS: Ninety-four cases of DLBCL followed up were selected in Fujian Tumor Hospital. The immunohistochemistry method was used to detect the protein expressions of BCL-2 BCL-6, MYC, CD10 and MUM-1, the gene abnormalities of MYC and BCL-2 were analyzed by fluorescence in situ hybridization, and the clinical pathological features and the related factors affecting prognosis in the patients with DLBCL were analyzed. RESULTS: The protein positive rates of BCL-2, BCL-6, MYC, CD10 and MUM-1 in 94 patients were 75.53% (71/94), 58.51% (55/94), 52.13% (49/94), 15.96% (15/94) and 34.04% (32/94) respectively. The detection rate of MYC gene abnormality was 20.93% (9/43) and the detection rate of BCL-2 gene abnormality was 44% (22/50); 2 kinds of gene abnormalities were of multiple copies, and 2 cases (2.13%) were abnormal in MYC and BCL-2 genes simultaneously. The median survival time of 3 years in 94 patients was 21.79 months (2-36 months), and the overall survival rates of 1 and 3 years were 82.98% and 64.89% respectively. Single factor analysis revealed that the high ECOG score (≥ 2), high international prognostic index (IPI) classification, positive expression of BCL-6 protein, and MYC and BCL-2 gene simultaneously abnormal were the risk factors influencing the prognosis (all P<0.05). COX regression analysis showed that IPI classification, ECOG score and treatment methods were independent factors influencing the prognosis (all P<0.05). CONCLUSION: IPI classification, ECOG score and treatment methods have greater impacts on the prognosis of patients with DLBCL. Chemotherapy combined with radiotherapy or surgical treatment can significantly improve the prognosis of patients.

Development of a selective and fast LC-MS/MS for determination of WSJ-537, an xanthine oxidase inhibitor, in rat plasma: Application to a pharmacokinetic study.

Gout is a common metabolic disorder caused by the deposition of monosodium urate crystals within joints. A new kind of xanthine oxidase inhibitor, WSJ-537, was developed as a potential drug. In order to investigate the pharmacokinetic behavior in vivo, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination the concentration of WSJ-537 in rat plasma was developed. After extraction by protein precipitation method with acetonitrile, the chromatographic separation was accomplished on a Venusil ASB C18 column(2.1mm×50mm, 3mm)at a flow rate of 0.3mLmin(-1) with the mobile phase consisting of acetonitrile-ammonium acetate (33:67, v/v). An electrospray ionization (ESI) source was applied and operated in the positive ion mode. The plasma concentration was detected by multiple reactions monitoring (MRM) mode with the target fragment ions m/z 410.2→m/z 368.1 for WSJ-537 and m/z 244.1→m/z 185.0 for the IS. Good linearity was observed in the range of 20-800ngmL(-1) (r=0.9947). The recovery of WSJ-537 in rats plasma was more than 85%. This method was suitable for pharmacokinetic studies after oral administration of 10mg/kg WSJ-537 in rats.

Simultaneous determination of six bioactive constituents of Guizhi Fuling Capsule in rat plasma by UHPLC-MS/MS: Application to a pharmacokinetic study.

A rapid and selective ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed for simultaneous determination of gallic acid, amygdalin, albiflorin, paeoniflorin, paeonol and cinnamic acid, the major bioactive constituents of Guizhi Fuling Capsule in rat plasma using phenacetin as internal standard (IS). The plasma samples were pretreated by protein precipitation with acetonitrile after acidification and separated on a Waters BEH C18 column (50mm×2.1mm, 1.7µm) using gradient elution with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile at a flow rate of 0.2mL/min. Mass spectrometric detection was performed on Micromass Quattromicro API mass spectrometer equipped with electrospray ionization source in multiple reaction monitoring (MRM) mode. The intra- and inter-day precisions (as relative standard deviation) were below 14.6% for all analytes, and the accuracies (as relative error) were within ±5.0%. The lower limits of quantification (LLOQ) were 10, 10, 5, 5, 25, 25ng/mL for gallic acid, amygdalin, albiflorin, paeoniflorin, paeonol and cinnamic acid, respectively. Extraction recovery, matrix effect and stability were satisfactory in rat plasma. This method was fully validated and applied to a pharmacokinetic study of the six bioactive constituents after oral administration of Guizhi Fuling Capsule to rats.

Influence of 5-HTR2A genetic polymorphisms on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis.

OBJECTIVE: The aim of the current meta-analysis was to assess the influence of common genetic polymorphisms in the 5-HTR2A gene on the efficacy of antidepressants in the treatment of major depressive disorder (MDD). METHOD: MEDLINE (1966-2013), Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013) and Chinese Biomedical Database (CBM) (1982-2013) were searched without language restrictions. Meta-analysis was performed using the STATA statistical software. We calculated the odds ratio (OR) and its 95% confidence interval (95% CI) to estimate the efficacy of antidepressants in the treatment of MDD. RESULTS: Eleven studies with a total of 1775 MDD patients met the inclusion criteria of this meta-analysis. Three common polymorphisms in the 5-HTR2A gene were assessed, including rs6311 C>T, rs7997012 G>A, and rs6313 T>C. Our findings suggested that the 5-HTR2A rs6313 T>C polymorphism was significantly correlated with a higher response rate to antidepressants in MDD patients (allele model: OR=1.33, 95% CI=1.05-1.68, P=0.020; dominant model: OR=1.62, 95% CI=1.21-2.18, P=0.001; homozygous model: OR=1.85, 95% CI=1.18-2.90, P=0.008). The rs7997012 G>A polymorphism was also associated with a higher response rate to antidepressants in MDD patients under the dominant model (OR=1.92, 95% CI=1.02-3.61, P=0.044). However, no significant correlation was found for the 5-HTR2A rs6311 C>T polymorphism under five genetic models (all P>0.05). CONCLUSION: Our findings provide empirical evidence that the 5-HTR2A rs6313 T>C and rs7997012 G>A polymorphism may be correlated with the efficacy of antidepressants in the treatment of MDD.