Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study

Background Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. Methods First, a simple and rapid liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC–MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. Results The LC–MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Conclusion Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies

Elucidation of the Differences in Cinobufotalin’s Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein

Cinobufotalin is one of the major anti-tumor components isolated from toad venom and has been used in the clinical therapy of hepatocellular carcinoma (HCC), known as Cinobufacini injection. However, the pharmacokinetic (PK) behaviors of cinobufotalin in vivo with HCC are still unknown. Hence, we have established a HCC model in Sprague Dawley (SD) rats induced by diethylnitrosamine (DEN), named as DEN-injured rats. Then, we developed and validated a sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify cinobufotalin in rat plasma. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of cinobufotalin in normal and DEN-injured rats after intravenous (i.v.) injection at a dosage of 2.5 mg/kg. Cinobufotalin pharmacokinetics was well described by the two-compartment pharmacokinetic model and the PK parameters were calculated using WinNonlin 3.3 software. The transfer rate constant of cinobufotalin from the central compartment to the peripheral compartment (k12) in DEN-injured rats was significantly greater than that in normal rats (p < 0.01), accompanied by the shorter half-life for the distribution phase (t1/2α). Additionally, the elimination rate constant (K10) and clearance (CL) values in DEN-injured rats were significantly higher than that in normal rats (p < 0.05 for K10 and p < 0.001 for CL, respectively). Therefore, the values of areas under concentration – time curve (AUC) and the liver concentration of cinobufotalin in DEN-injured rats was obviously lower than that in normal rats (p < 0.001 and p < 0.01, respectively). This indicated that the PK behaviors of cinobufotalin will be altered in rats with HCC. In addition, P-glycoprotein (P-gp) has shown higher expression in live tissues of DEN-injured rats. Furthermore, cinobufotalin was identified as the substrate of P-gp using MDCK II and MDCK-MDR1 cell models for the first time. Consequently, P-gp will play an important role in the disposition of cinobufotalin in vivo, which provided a new combination therapy for the clinical treatment of HCC

Assessing Reproducibility of Inherited Variants Detected With Short-Read Whole Genome Sequencing

Background: Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. Results: To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when \u3e 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×. Conclusions: Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS

Assessing reproducibility of inherited variants detected with short-read whole genome sequencing

Background: Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. Results: To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30x. Conclusions: Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.Peer reviewe

Dual-Vth leakage reduction with Fast Clock Skew Scheduling Enhancement

Dual-Vth technique is a mature and effective method for reducing leakage power consumption. Previously proposed algorithms assign logic gates with sufficient timing slack to high threshold voltage to reduce leakage power without impact on timing. Meanwhile, clock skew scheduling algorithms are always utilized to optimize period or timing slack. In order to further reduce subthreshold leakage power consumption, in this paper, we ingeniously combine dual voltage assignment technique with intended clock skew scheduling: First, a leakage weight based clock skew scheduling algorithm is proposed to enlarge the leakage power optimization potential. Then we employ a dual-threshold voltage assignment algorithm to minimize leakage power. The experimental results on ISCAS89 benchmark circuits show that, within only several seconds, the leakage power can be further reduced by as much as 41.30% and by 9.87% on average with this new approach, compared to using the traditional method without considering clock skews. Three timing optimized industrial circuit blocks, among which each has around one hundred thousand gates, have also been optimized. It is shown that an average leakage power reduction of 9.95% can be achieved within minutes compared with traditional techniques. ? 2010 EDAA.EI

The complete chloroplast genome of Hosta plantaginea (Lam.) Aschers

Hosta plantaginea is an important ornamental and horticultural plant endemic to China. In this study, we generated complete chloroplast genome of H. plantaginea using high-throughput sequencing. The complete chloroplast sequence is a circular molecule of 157,091 bp in size, consisting of a large single copy (LSC, 86,061 bp) and a small single copy (SSC; 18,282 bp) separated by a pair of inverted repeats (IRs; 26,374 bp), The total GC content is 37.8%, with 35.9, 31.7, and 43.0% in LSC, SSC, and IRs, respectively. A total of 132 genes are annotated, including 84 protein-coding genes, 38 tRNAs, 8 rRNAs, and 2 pseudogenes. The phylogenetic analysis revealed that H. plantaginea was formed to be the early diverging species within Hosta

Silencing of Paternally Expressed Gene 10 Inhibits Trophoblast Proliferation and Invasion.

Paternally expressed gene 10 (PEG10) is an imprinted and monoallelic expressed gene. Previous study using a knockout mouse model revealed a crucial role of PEG10 in placental development, yet the exact function of PEG10 during placentation remains to be elucidated. In this study, denuded chorionic villi were prepared from first trimester human placentas, and transduced with PEG10 small interference RNA (siRNA) or non-targeting control sequence by lentiviral infection. Immunohistochemical staining revealed that silencing of PEG10 in the chorionic villous explants resulted in reduced immune-reactivity to CK7, Ki67 and integrin α5, implying that silencing of PEG10 impaired the proliferation of villous trophoblasts and may interfere with the activity of extravillous trophoblasts. We further investigated the role of PEG10 in the proliferation, migration and invasion of JEG-3 trophoblast cell line and the primary chorionic villous cells. PEG10-silenced JEG-3 cells and primary chorionic villous cells displayed a reduced proliferation rate and impaired invasiveness in vitro. Silencing of PEG10 in trophoblast cells led to upregulated expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) as well as downregulated expression of matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, knockdown of TIMP-1 reversed the suppressed invasiveness of PEG10 siRNA-transduced JEG-3 cells. In conclusion, our study demonstrates that PEG10 plays an important role in trophoblast proliferation and promotes trophoblast invasion through TIMP-1

Research on beam supply control strategy based on sliding mode control

In the hybrid multiple H-bridge topology of beam supply, the load change of a DC/DC full-bridge converter can greatly affect the output voltage during onsite operation. An improved sliding mode control (SMC) strategy is thus proposed in this paper, where the rate of switching control is added to the law of system equivalent control to create a law that can realize a complete sliding mode control. Considering the special operating conditions of the load can have an influence on the performance of the controller, the impact of uncertainty existing in onsite conditions is suppressed with the proposed strategy utilized. The validity of the proposed strategy, finally, is verified by simulation, which proves the outperformance of the system in both robustness and dynamics