Relationship between serum concentration and clinical response of quetiapine in adolescents and adults with bipolar disorders in acute stage: a prospective observational study.

BACKGROUND: It is found that there are great differences in the efficacy of quetiapine at the same dose in many patients with bipolar disorders. Therefore, therapeutic drug monitoring (TDM) is a valuable tool for guiding treatment with quetiapine. The aims of this study were to assess the relationship between serum concentration and clinical response of quetiapine in adolescents and adults with bipolar disorders in acute stage. METHODS: The study design was prospective and observational. Within the naturalistic setting of a routine TDM service at the First Affiliated Hospital, Zhejiang University School of Medicine. Psychiatric symptoms were assessed using the HAMD (Hamilton Depression Scale), YRMS (Young manic rating scale) and CUDOS-M (Clinically Useful Depression Outcome Scale-Mixed Subscale). The decline of HAMD and YMRS scores was were used to assess clinical outcome of bipolar disorders respectively. RESULTS: 169 inpatients (23.7 % male, 76.3 % female) were enrolled in the study. We found that there was a strong correlation between quetiapine serum concentrations and clinical outcomes (rs = 0.702, p < 0.001). While, quetiapine daily dose was not correlated with clinical outcome. We found that when the quetiapine serum level is >146.85 ng/ml in depression episodes patients could obtain a satisfactory treatment effect after 2 weeks of hospitalization. CONCLUSIONS: We found a significant positive relationship between serum concentration and clinical outcome, and also determined the serum concentration of quetiapine for the treatment of bipolar depression.

Identification of differentially methylated genes as diagnostic and prognostic biomarkers of breast cancer.

BACKGROUND: Aberrant DNA methylation is significantly associated with breast cancer. METHODS: In this study, we aimed to determine novel methylation biomarkers using a bioinformatics analysis approach that could have clinical value for breast cancer diagnosis and prognosis. Firstly, differentially methylated DNA patterns were detected in breast cancer samples by comparing publicly available datasets (GSE72245 and GSE88883). Methylation levels in 7 selected methylation biomarkers were also estimated using the online tool UALCAN. Next, we evaluated the diagnostic value of these selected biomarkers in two independent cohorts, as well as in two mixed cohorts, through ROC curve analysis. Finally, prognostic value of the selected methylation biomarkers was evaluated breast cancer by the Kaplan-Meier plot analysis. RESULTS: In this study, a total of 23 significant differentially methylated sites, corresponding to 9 different genes, were identified in breast cancer datasets. Among the 9 identified genes, ADCY4, CPXM1, DNM3, GNG4, MAST1, mir129-2, PRDM14, and ZNF177 were hypermethylated. Importantly, individual value of each selected methylation gene was greater than 0.9, whereas predictive value for all genes combined was 0.9998. We also found the AUC for the combined signature of 7 genes (ADCY4, CPXM1, DNM3, GNG4, MAST1, PRDM14, ZNF177) was 0.9998 [95% CI 0.9994-1], and the AUC for the combined signature of 3 genes (MAST1, PRDM14, and ZNF177) was 0.9991 [95% CI 0.9976-1]. Results from additional validation analyses showed that MAST1, PRDM14, and ZNF177 had high sensitivity, specificity, and accuracy for breast cancer diagnosis. Lastly, patient survival analysis revealed that high expression of ADCY4, CPXM1, DNM3, PRDM14, PRKCB, and ZNF177 were significantly associated with better overall survival. CONCLUSIONS: Methylation pattern of MAST1, PRDM14, and ZNF177 may represent new diagnostic biomarkers for breast cancer, while methylation of ADCY4, CPXM1, DNM3, PRDM14, PRKCB, and ZNF177 may hold prognostic potential for breast cancer.

Hydroxychloroquine potentiates the anti-cancer effect of bevacizumab on glioblastoma via the inhibition of autophagy.

Bevacizumab (BEV) is widely used for the treatment of patients with recurrent glioblastoma (GBM), but recent evidence demonstrated that BEV induced cytoprotective autophagy, which allows tumor cells to survive. Hydroxychloroquine (HCQ) inhibits lysosomal acidification and blocks autophagy via influencing autophagosome fusion and degradation. HCQ is often used to enhance the efficacy of chemoradiotherapy. However, whether HCQ sensitizes GBM cells to BEV and the molecular mechanism of this effect are not clear. We showed that high concentrations of BEV increased the LC3-II/LC3-I ratio and caused the degradation of Beclin1 in the LN18 and LN229 cell lines, indicating that high concentrations of BEV induced the autophagy of the LN18 and LN229 cells. However, BEV (100 µg/ml) did not influence the autophagy of the LN18 and LN229 cells, and HCQ at less than 5 µg/ml significantly accumulated LC3B-II and p62 proteins and blocked the autophagy process. Importantly, we found that HCQ (5 µg/ml) potentiated the anti-cancer effect of BEV (100 µg/ml). Therefore, HCQ is a novel strategy that may augment the efficacy of BEV for GBM via the inhibition of autophagy.

Effects of root phenotypic changes on the deep rooting of Populus euphratica seedlings under drought stresses.

BACKGROUND: Deep roots are critical for the survival of Populus euphratica seedlings on the floodplains of arid regions where they easily suffer drought stress. Drought typically suppresses root growth, but P. euphratica seedlings can adjust phenotypically in terms of root-shoot allocation and root architecture and morphology, thus promoting deep rooting. However, the root phenotypic changes undertaken by P. euphratica seedlings as a deep rooting strategy under drought conditions remain unknown. METHODS: We quantified deep rooting capacity by the relative root depth (RRD), which represents the ratio of taproot length to plant biomass and is controlled by root mass fraction (RMF), taproot mass fraction (TRMF), and specific taproot length (STRL). We recorded phenotypic changes in one-year-old P. euphratica seedlings under control, moderate and severe drought stress treatments and assessed the effects of RMF, TRMF, and STRL on RRD. RESULTS: Drought significantly decreased absolute root depth but substantially increased RRD via exerting positive effects on TRMF, RMF, and STRL. Under moderate drought, TRMF contributed 55%, RMF 27%, and STRL 18% to RRD variation. Under severe drought, the contribution of RMF to RRD variation increased to 37%, which was similar to the 41% for TRMF. The contribution of STRL slightly increased to 22%. CONCLUSION: These results suggest that the adjustments in root architecture and root-shoot allocation were predominantly responsible for deep rooting in P. euphratica seedlings under drought conditions, while morphological changes played a minor role. Moreover, P. euphratica seedlings rely mostly on adjusting their root architecture to maintain root depth under moderate drought conditions, whereas root-shoot allocation responds more strongly under severe drought conditions, to the point where it plays a role as important as root architecture does on deep rooting.

[4, 8-disubstituted-8, 9-dihydro-pyrazine[2,3-g]quinazoline-7(6H)-ketones: a novel class of antitumor agents].

OBJECTIVE: To evaluate the antitumor activity of a novel class of 4, 8-Disubstituted-8, 9-dihydropyrazine[2, 3-g]quinazoline-7(6H)-ketones in vitro, and to screen potential anticancer compounds for further study. METHODS: Seventeen compounds of 4, 8-Disubstituted-8, 9-dihydropyrazine[2, 3-g]quinazoline-7(6H)-ketones were synthesized with solid-phase method for biological evaluation of EGFR tyrosine kinase. MTT method was used to evaluate the cytotoxic activity in vitro against three human cancer cell lines (human lung carcinoma cell line A549, human leukemia cell lines K562 and human gastric carcinoma cell line SGC7901). RESULTS: Compound 7-13 and 7-14 showed potent antitumor activities against A549 cells, with IC(50) values of 8.10 and 8.12 mol/L, respectively. Eight compounds showed proliferative inhibition effect on K562 cells, especially 7-2, 7-13 and 7-17, with IC(50) values of 2.22,0.57 and 7.20 mol/L,respectively.And compound 7-13 and 7-3 showed potent antitumor activity against SGC7901 cells, with IC(50) values of 4.20 and 9.71 mol/L, respectively. CONCLUSION: The synthesized compounds 4, 8-Disubstituted-8, 9-dihydropyrazine[2, 3-g] quinazoline-7(6H)-ketones show inhibition effects on human cancer cell lines in vitro. Compound 7-13 has anticancer activity in all three cancer cell lines, which might be used as a potential antitumor drug for further study.

[Rat microsomal glutathione S-transferase 1 alters cytotoxic effects of chlorambucil on PC-3, K562, HepG2 and P388D1 cell lines].

OBJECTIVE: To explore the possible association between activation of rat microsomal glutathione S-transferase 1 (mGST1) and chlorambucil toxicity on selected cancer cell lines. METHODS: Hepatic microsomes were prepared from male Sprague-Dawley rats and washed to remove cytosolic contamination. mGST1 was purified and its activity was measured. PC-3, K562, HepG2 and P388D1 cell lines were exposed to chlorambucil (CHB) alone or to CHB with mGST1 at concentrations of 0 ~ 100 micromol/L for 8, 24, 48, 72 h. Cytotoxic effects of CHB were determined by cell growth inhibition (MTT assay), mitochondrial transmembrane potential (DeltaPsim), and fluorescence morphological examination (AO/EB staining). RESULTS: The decreased cytotoxic effects of CHB on the cell lines altered by mGST1 were demonstrated in concentration- and time-dependant manners. The CHB-induced apoptosis on PC-3 and K562 cell lines altered by mGST1 was confirmed using DeltaPsim examination, JC-1 or AO/EB staining. CONCLUSION: mGST1 can reduce the cytotoxic effects of CHB in selected cancer cell lines.