Assessment of the Utility of Physiologically-based Pharmacokinetic Model for prediction of Pharmacokinetics in Chinese and Japanese Populations.

The objective for the present analyses was to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling for prediction of the pharmacokinetics (PK) in Chinese and Japanese populations with a panel of Pfizer internal compounds. Twelve compounds from Pfizer internal development pipeline with available Westerner PK data and available PK data in at least one of the subpopulations of Japanese and Chinese populations were identified and included in the current analysis. These selected compounds represent various elimination pathways across different therapeutic areas. The Simcyp® PBPK simulator was used to develop and verify the PBPK models of individual compounds. The developed models for these compounds were verified by using the clinical PK data in Westerners. The verified PBPK models were further used to predict the PK of these compounds in Chinese and Japanese populations and the predicted PK parameters were compared with the observed PK parameters. Ten of the 12 compounds had PK data in Chinese, and all the 12 compounds had PK data in Japanese. In general, the PBPK models performed well in predicting PK in Chinese and Japanese, with 8 of 10 drugs in Chinese and 7 of 12 drugs in Japanese has AAFE values less than 1.25-fold. PBPK-guided predictions of the relative PK difference were successful for 75% and 50%, respectively, between Chinese and Western and between Japanese and Western of the tested drugs using 0.8-1.25 as criteria. In conclusion, well verified PBPK models developed using data from Westerners can be used to predict the PK in Chinese and Japanese populations.

Long non-coding RNA SNHG17 promotes proliferation, migration and invasion of glioma cells by regulating the miR-23b-3p/ZHX1 axis.

BACKGROUND: Long non-coding RNA (lncRNA) small nucleolar RNA host gene 17 (SNHG17) is a carcinogenic lncRNA in diverse cancers. The expression pattern and mechanisms of SNHG17 in glioma still await verification. METHODS: Paired glioma samples were enrolled. SNHG17, miR-23b-3p, and zinc-fingers and homeoboxes 1 (ZHX1) mRNA expression were examined by a quantitative real-time polymerase chain reaction (qRT-PCR). SNHG17 short hairpin RNA (shRNA) and miR-23b-3p mimics were transfected into LN229 and U251 cell lines to repress SNHG17 and up-regulate miR-23b-3p expression, respectively. Proliferation, migration and invasion of LN229 and U251 cells were probed by a cell counting kit-8 assay and a Transwell assay. Bioinformatics prediction, dual-luciferase reporter assay, RNA immunoprecipitation assay, qRT-PCR and western blotting were applied to determine the regulatory relationships among SNHG17, miR-23b-3p and ZHX1. RESULTS: SNHG17 expression was markedly raised in glioma tissues, which was positively correlated with ZHX1 expression and negatively associated with the expression of miR-23b-3p. After transfection of SNHG17 shRNAs into glioma cells, the proliferation, migration and invasion of cancer cells was markedly restrained. miR-23b-3p mimics the function of SHNG17 knockdown. Furthermore, miR-23b-3p was shown to be negatively modulated by SNHG17, and ZHX1 was identified as a target of miR-23b-3p. CONCLUSIONS: SNHG17 is a "competing endogenous RNA" with respect to modulating ZHX1 expression by adsorbing miR-23b-3p and thereby promoting glioma progression.

[The pharmacodynamic research on fuxiye, a Chinese herbal lotion for external wash].

OBJECTIVE: To observe antisepsis, anti-swelling, and therapeutic effects of Fuxiye (FXY), a Chinese medical lotion for external wash in treating vaginitis model rats. METHODS: The cervicitis rat model was induced by agar plate diffusion, ear auricle swelling induced by dimethylbenzene, and chemical stimulus. The in vitro antibiotic actions of FXY were observed. Besides, its effects on the swelling and inflammation in model rats were also observed. RESULTS: FXY at 25 mg/mL could completely inhibit the growth of Pseudomonas aeruginosa, Escherichia coli, pyogenic Streptococcus, and Streptococcus agalactiae. FXY at 50 mg/mL could completely inhibit the growth of Staphylococcus aureus and Candida albicans. It obviously restrained dimethylbenzene induced ear auricle swelling. It significantly alleviated cervicitis induced by chemical stiumli. CONCLUSION: FXY showed better effects on antisepsis, anti-inflammation, and treating cervicitis.

Membrane Protein Bcest Is Involved in Hyphal Growth, Virulence and Stress Tolerance of Botrytis cinerea.

Botrytis cinerea is a necrotrophic model fungal plant pathogen that causes grey mould, a devastating disease responsible for large losses in the agriculture sector. As important targets of fungicides, membrane proteins are hot spots in the research and development of fungicide products. We previously found that membrane protein Bcest may be closely related to the pathogenicity of Botrytis cinerea. Herein, we further explored its function. We generated and characterised ΔBcest deletion mutants of B. cinerea and constructed complemented strains. The ΔBcest deletion mutants exhibited reduced conidia germination and germ tube elongation. The functional activity of ΔBcest deletion mutants was investigated by reduced necrotic colonisation of B. cinerea on grapevine fruits and leaves. Targeted deletion of Bcest also blocked several phenotypic defects in aspects of mycelial growth, conidiation and virulence. All phenotypic defects were restored by targeted-gene complementation. The role of Bcest in pathogenicity was also supported by reverse-transcriptase real-time quantitative PCR results indicating that melanin synthesis gene Bcpks13 and virulence factor Bccdc14 were significantly downregulated in the early infection stage of the ΔBcest strain. Taken together, these results suggest that Bcest plays important roles in the regulation of various cellular processes in B. cinerea.

Electrocardiogram features of premature ventricular contractions/ventricular tachycardia originating from the left ventricular outflow tract and the treatment outcome of radiofrequency catheter ablation.

BACKGROUND: Radiofrequency catheter ablation (RFCA) has been used for the ablation of premature ventricular contractions (PVCs) or ventricular tachycardia (VT). To date, the mapping and catheter ablation of the arrhythmias originating from the left ventricular outflow tract (LVOT) has not been specified. This study investigates the electrocardiogram (ECG) feature of PVCs or VT originating from the LVOT. Moreover, the treatment outcome of RFCA is analyzed. METHODS: Mapping and ablation were performed on the supravalvular or subvalvular aorta in 52 cases with PVCs/VT originating from the LVOT. The data were compared with those from 104 patients with PVCs/VT originating from the right ventricular outflow tract (RVOT). A differential procedure was prepared based on the comparison of the ECG features of PVCs/VT originating from the RVOT, LVOT, and their different parts. RESULTS: Among 52 cases with PVCs originating from the LVOT, 47 were successfully treated by RFCA, with a success rate of 90.38%. Several differences among the 12-lead ECG features were observed from the RVOT and LVOT in the left and right coronary sinus groups, as well as under the left coronary sinus group (left fibrous trigone): (1) If the precordial leads transition 0 are considered as the diagnostic parameters of PVCs/VT originating from the LVOT, then the sensitivity, specificity, as well as positive and negative predictive values are 94.12%, 93.00%, 87.27%, and 96.88%, respectively; (2) The analysis of different subgroups of the LVOT are as follows: (a) A mainly positive wave of r or m pattern was recorded in the lead I in 72.73% of patients in the right coronary sinus group, versus 12.90% of patients in the left coronary sinus group, and 0% in the under left coronary sinus group. (b) All patients in the right coronary sinus group presented waves of RII>RIII and QSaVR>QSaVL, whereas most patients in the other two groups showed waves of RIII>RII and QSaVL>QSaVR. (c) Most patients in the under left coronary sinus group in lead V1 had a mainly positive wave (R) (77.78%), whereas those in the right (81.82%) and left (62.50%) coronary sinus groups had mainly negative waves (rS). CONCLUSIONS: RFCA is a safe and effective curative therapy for PVCs/VT originating from the LVOT. The 12-lead ECG features of the LVOT from different origins exhibit certain distinctions.

Prognostic value of hypoalbuminemia at diagnosis in de novo non-M3 acute myeloid leukemia.

The association between serum albumin level and clinical outcomes has been reported for several hematological malignancies. Our study aimed to identify the relationship between serum albumin level at the time of diagnosis and subsequent clinical outcomes in patients with newly diagnosed acute myeloid leukemias (AMLs) other than acute promyelocytic leukemias (APLs). A total of 243 patients with de novo non-M3 AML were enrolled in this study. Variables including gender, age, serum albumin, white blood cell (WBC) count, hemoglobin (Hb), platelet (PLT) count, blasts at peripheral blood (PB) and bone marrow (BM), immunophenotype and cytogenetics at diagnosis, BM response after one course of chemotherapy and hematopoietic stem cell transplantation (HSCT) treatment were studied. We found that normal albumin level (serum albumin >3.5 g/dL) was significantly associated with superior overall survival (HR = 0.375, p < .001) and leukemia-free survival (HR = 0.411, p < .001). These results demonstrate that albumin could serve as a simple, cheap, and objective prognostication factor in refinement of AML regimens.

Cytosolic ß-glucosidase inhibition and renal blood flow suppression are leading causes for the enhanced systemic exposure of salidroside in hypoxic rats.

The promising benefits of salidroside (SAL) in alleviating high altitude sickness boost investigations on its pharmacokinetics and biological activity. However, the transportation and disposition process of SAL under hypoxic conditions has never been explored. The current study was proposed to investigate the pharmacokinetics of SAL in hypoxic rats and to explore the underlying mechanisms for the distinct metabolic fate of SAL under hypoxia. Pharmacokinetic studies on SAL was conducted in both hypoxic and normoxic rats. The transport properties of SAL were investigated on both hypoxic and normoxic Caco-2 monolayer models. Enzymes involved in SAL metabolism were identified and the effects of hypoxia on these enzymes were assessed by real-time PCR, western blotting analyses, and rat liver homogenate incubation. The renal clearance (CLr) of SAL, effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in both hypoxic and normoxic rats were also determined for renal function assessment. It was found that the systemic exposure of SAL in hypoxic rats was remarkably higher than that in normoxic rats. The barrier function of Caco-2 monolayer was weakened under hypoxia due to the impaired brush border microvilli and decreased expression of tight junction protein. Hepatic metabolism of SAL in hypoxic rats was attenuated due to the reduced activity of cytosolic ß-glucosidase (CBG). Moreover, CLr of SAL was reduced in hypoxic rats due to the suppressed ERPF. Our findings suggest the potential need for dose-adjustment of SAL or its structural analogs under hypoxic conditions.

Bloodstream Infections Caused by Klebsiella pneumoniae Carbapenemase 2-producing K. pneumoniae at a Hematology Department in Wenzhou, China.

The increasing prevalence of Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae (KPC-2-KP) infections can become a new life-threatening complication for hematological patients. Five cases of KPC-2-KP bloodstream infections have been identified in our hematology department over the past 10 years. The current treatment options do not show satisfactory efficacy, especially for bloodstream infections. The treatment of these five cases was unsuccessful, mainly due to the high minimum inhibitory concentrations of carbapenem, fosfomycin resistance, or the inaccessibility of polymyxin. Further investigations into the optimal treatment modalities are therefore imperative. The present study provides insights into the epidemiology and clinical challenges of treating KPC-2-KP bloodstream infections.

MLL2 protein is a prognostic marker for gastrointestinal diffuse large B-cell lymphoma.

Mixed linage leukemia gene 2 (MLL2) is identified as a novel mutation gene in diffuse large B cell lymphoma (DLBCL). However, the significance of MLL2 protein expression for the prognosis of DLBCL is unclear. In this study, we detected MLL2 protein expression in primary gastrointestinal diffuse large B cell lymphoma (PGI-DLBCL) samples by using tissue microarray immunohistochemistry, and analyzed the correlation between MLL2 protein expression and tumor proliferation activity. In addition, we investigated clinical significance of MLL2 protein expression for PGI-DLBCL prognosis. We found that there was significant difference in MLL2 protein expression between PGI-DLBCL and reactive hyperplasia of lymph node. High expression of MLL2 protein indicated higher clinical stage. In older patients (>60 years) with PGI-DLBCL, MLL2 protein expression was positively correlated with Ki-67 expression and negatively correlated with patient survival. Our data suggest that MLL2 protein is overexpressed in PGI-DLBCL and appears as a prognostic factor for patients of PGI-DLBCL, especially for those older than 60 years old.

Multiplex reverse transcription loop-mediated isothermal amplification for the simultaneous detection of CVB and CSVd in chrysanthemum.

A multiplex reverse transcription loop-mediated isothermal amplification (mRT-LAMP) assay was developed for the simultaneous detection of Chrysanthemum Virus B (CVB) and Chrysanthemum stunt viroid (CSVd), which are the major viral pathogens of chrysanthemum worldwide. Two sets of mRT-LAMP primers were designed for the coat protein gene of CVB and the complete nucleotide sequence of CSVd, and a restriction enzyme cleavage site was inserted into two pairs of species-specific primers. The mRT-LAMP assay was designed by combining these two sets for a total of eight primers. The mRT-LAMP method distinguished between CVB and CSVd due to the subsequent restriction enzyme analysis. The sensitivity of the mRT-LAMP method was 10(3) times higher than classical PCR regarding the detection limits for CVB and CSVd. No positive results were observed when RNA from other chrysanthemum pathogens were used as mRT-LAMP templates. The method was verified by testing chrysanthemum samples collected from Beijing and Henan Province and showed high reliability and sensitivity. The developed mRT-LAMP assay also offers an efficient, convenient, and rapid tool for screening chrysanthemum virus and viroid, especially CVB and CSVd, and can be diagnosed in a single reaction. These results suggest that the new mRT-LAMP method may be used routinely for virus and viroid surveys.