Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells.

The scarcity of tissue-specific stem cells and the complexity of their surrounding environment have made molecular characterization of these cells particularly challenging. Through single-cell transcriptome and weighted gene co-expression network analysis (WGCNA), we uncovered molecular properties of CD133(+)/GFAP(-) ependymal (E) cells in the adult mouse forebrain neurogenic zone. Surprisingly, prominent hub genes of the gene network unique to ependymal CD133(+)/GFAP(-) quiescent cells were enriched for immune-responsive genes, as well as genes encoding receptors for angiogenic factors. Administration of vascular endothelial growth factor (VEGF) activated CD133(+) ependymal neural stem cells (NSCs), lining not only the lateral but also the fourth ventricles and, together with basic fibroblast growth factor (bFGF), elicited subsequent neural lineage differentiation and migration. This study revealed the existence of dormant ependymal NSCs throughout the ventricular surface of the CNS, as well as signals abundant after injury for their activation.

Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation.

Higher-order chromosomal organization for transcription regulation is poorly understood in eukaryotes. Using genome-wide Chromatin Interaction Analysis with Paired-End-Tag sequencing (ChIA-PET), we mapped long-range chromatin interactions associated with RNA polymerase II in human cells and uncovered widespread promoter-centered intragenic, extragenic, and intergenic interactions. These interactions further aggregated into higher-order clusters, wherein proximal and distal genes were engaged through promoter-promoter interactions. Most genes with promoter-promoter interactions were active and transcribed cooperatively, and some interacting promoters could influence each other implying combinatorial complexity of transcriptional controls. Comparative analyses of different cell lines showed that cell-specific chromatin interactions could provide structural frameworks for cell-specific transcription, and suggested significant enrichment of enhancer-promoter interactions for cell-specific functions. Furthermore, genetically-identified disease-associated noncoding elements were found to be spatially engaged with corresponding genes through long-range interactions. Overall, our study provides insights into transcription regulation by three-dimensional chromatin interactions for both housekeeping and cell-specific genes in human cells.

Investigating the therapeutic effects and mechanisms of Roxadustat on peritoneal fibrosis Based on the TGF-ß/Smad pathway.

Peritoneal fibrosis (PF) is particularly common in individuals undergoing peritoneal dialysis (PD). Fibrosis of the parenchymal tissue typically progresses slowly. Therefore, preventing and reducing the advancement of fibrosis is crucial for effective patient treatment. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), primarily used to treat and improve renal anemia. Recent studies have found that HIF-1α possesses antioxidant activity and exerts a certain protective effect in ischemic heart disease and spinal cord injury, while it can also delay the progression of pulmonary and renal fibrosis. This study establishes the mice model through intraperitoneal injection of 4.25 % peritoneal dialysate fluid (PDF) and explores the therapeutic effects of Roxadustat by inducing TGF-ß1-mediated epithelial-mesenchymal transition (EMT) in Met-5A cells. The aim is to investigate the protective role and mechanisms of Roxadustat against PD-related PF. We observed thicker peritoneal tissue and reduced permeability in animals with PD-related PF samples. This was accompanied by heightened inflammation, which Roxadustat alleviated by lowering the levels of inflammatory cytokines (IL-6, TNF-α). Furthermore, Roxadustat inhibited EMT in PF mice and TGF-ß1-induced Met-5A cells, as evidenced by decreased expression of fibrotic markers, such as fibronectin, collagen I, and α-SMA, alongside an elevation in the expression of the epithelial marker, E-cadherin. Roxadustat also significantly decreased the expression of TGF-ß1 and the phosphorylation of p-Smad2 and p-Smad3. In conclusion, Roxadustat ameliorates peritoneal fibrosis through the TGF-ß/Smad pathway.

The pharmacokinetics/pharmacodynamics of ceftazidime/avibactam for central nervous system infections caused by carbapenem-resistant Gram-negatives: a prospective study.

OBJECTIVES: To describe the pharmacokinetics/pharmacodynamics (PK/PD) of ceftazidime/avibactam in critically ill patients with CNS infections. METHODS: A prospective study of critically ill patients with CNS infections who were treated with ceftazidime/avibactam and the steady-state concentration (Css) of ceftazidime/avibactam in serum and/or CSF was conducted between August 2020 and May 2023. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of ceftazidime/avibactam was evaluated. RESULTS: Seven patients were finally included. The ceftazidime/avibactam target attainment in plasma was optimal for three, quasi-optimal for one and suboptimal for three. In three patients with CSF drug concentrations measured, ceftazidime/avibactam target attainment in CSF was 100% (3/3), which was optimal. The AUCCSF/serum values were 0.59, 0.44 and 0.35 for ceftazidime and 0.57, 0.53 and 0.51 for avibactam. Of the seven patients, 100% (7/7) were treated effectively, 71.4% (5/7) achieved microbiological eradication, 85.7% (6/7) survived and 14.3% (1/7) did not survive. CONCLUSIONS: The limited clinical data suggest that ceftazidime/avibactam is effective in the treatment of CNS infections caused by MDR Gram-negative bacilli (MDR-GNB), can achieve the ideal drug concentration of CSF, and has good blood-brain barrier penetration.

Population pharmacokinetics and dosage optimization of linezolid in Chinese older patients.

PURPOSE: To assess the pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of hospitalized Chinese older patients. METHODS: Patients > 60 years of age, who received intravenous linezolid (600 mg), were included. A population pharmacokinetics (PPK) model was established using nonlinear mixed-effects modeling. The predictive performance of the final model was assessed using goodness-of-fit plots, bootstrap analyses, and visual predictive checks. Monte Carlo simulations were used to evaluate the achievement of a pharmacodynamics target for the area under the serum concentration-time curve/minimum inhibitory concentration (AUC0-24/MIC). RESULTS: A total of 210 samples were collected from 120 patients. A one-compartment PPK model with linear elimination best predicted the linezolid plasma concentrations. Linezolid clearance (CL) was 4.22 L h-1 and volume of distribution (Vd) was 45.80 L; serum uric acid (SUA) was a significant covariate of CL. CONCLUSION: The results of this study indicated that the standard dose was associated with a risk of overexposure in older patients, particularly those with high SUA values; these patients would benefit from a lower dose (300 mg every 12 h).

Study on the active components and mechanism of Atractylodis Macrocephalae Rhizoma for invigorating the spleen and tonifying qi based on spectrum-effect relationship and network pharmacology.

Spleen deficiency can lead to various abnormal physiological functions of the spleen. Atractylodis Macrocephalae Rhizoma (AMR) is a traditional Chinese medicine used to invigorate the spleen and tonify qi. The study aimed to identify the primary active components influencing the efficacy of AMR in strengthening the spleen and replenishing qi through spectrum-effect relationship and chemometrics. Network pharmacology was used to investigate the mechanism by which AMR strengthens the spleen and replenishes qi, with molecular docking utilized for validation purposes. The findings indicated that bran-fried AMR exhibited superior efficacy, with atractylenolides and atractylone identified as the primary active constituents. Atractylenolide II emerged as the most influential component impacting the effectiveness of AMR, while the key target was androgen receptor. Furthermore, crucial pathways implicated included the mitogen-activated protein cascade (MAPK) cascade, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding, and RNA polymerase II sequence-specific DNA-binding transcription factor binding. In summary, our study has identified the primary active components associated with the efficacy of AMR and has provided an initial exploration of its mechanism of action. This offers a theoretical foundation for future investigations into the material basis and molecular mechanisms underlying the pharmacodynamics of AMR.

Phenylacetyl glutamine (PAGln) enhances cardiomyocyte death after myocardial infarction through ß1 adrenergic receptor.

This study aims to explore the roles of phenylacetyl glutamine (PAGln) on myocardial infarction (MI) pathogenesis. Here, using targeted metabolomics analysis, it was found that the plasma metabolite PAGln was upregulated in coronary artery disease (CAD) patients and MI mice and could be an independent risk factor for CAD. In vivo and in vitro functional experiments revealed that PAGln pretreatment enhanced MI-induced myocardial injury and cardiac fibrosis, as evident by the increased infarct size, cardiomyocyte death, and the upregulated expression of cardiac fibrosis markers (Col1a1 and α-SMA). Combined with RNA-sequencing analysis and G protein-coupled receptor (GPCR) inhibitor, we found that the GPCR signaling activation is essential for PAGln-mediated effects on cardiomyocyte death. Furthermore, drug affinity responsive target stability and cellular thermal shift assay demonstrated that PAGln could interact with ß1-adrenergic receptor (AR). Moreover, ß1-AR blocker treatment indeed extended the cardiac remodeling after PAGln-enhanced MI. These results suggest that PAGln might be a potential therapeutic target for extending the cardiac remodeling window in MI patients that signals via ß1-AR.

Determination of polyamines in urine via electrospun nanofibers-based solid-phase extraction coupled with GC-MS and application to gastric cancer patients.

The simultaneous determination of polyamines and their metabolites in urine samples was achieved by gas chromatography-mass spectrometry in the selected ion monitoring mode. After conjugating with the ion-pair reagent bis-2-ethylhexylphosphate in the aqueous phase, the polyamines in the samples were extracted with polystyrene nanofiber-based packed-fiber solid-phase extraction followed by a derivatization step using pentafluoropropionyl anhydride. With optimal conditions, all analytes were separated well. For analytes of putrescine, cadaverine, N-acetylputrescine, and N-acetylcadaverine, the linearity was good in the range of 0.05-500 µmol/L (R2  ≥ 0.993). While for spermidine, spermine, acetylspermidine, N8 -acetylspermidine, and N-acetylspermine, the linearity was good in the range of 0.5-500 µmol/L (R2  ≥ 0.990). The recoveries of three spiked concentrations (0.5, 5, 300 µmol/L) were 85.6%-108.4%, and relative standard deviations for intra- and interday were in the range of 2.9%-13.4% and 4.5%-15.1%, respectively. The method was successfully applied to the analysis of urine samples of gastric cancer patients. The results showed that the levels of most polyamines and N-acetylated polyamines from the patient group were significantly higher than those from the control group. The altered concentrations of the above-mentioned metabolites suggest their role in the pathogenesis of gastric cancer, and they should be further evaluated as potential markers of gastric cancer.

Bioinspired low-density lipoprotein co-delivery system for targeting and synergistic cancer therapy.

Epithelial-mesenchymal transition (EMT) is the culprit of tumor invasion and metastasis. As a critical transcription factor that induces EMT, snail is of great importance in tumor progression, and knocking down its expression by small interfering RNA (siRNA) may inhibit tumor metastasis. Herein, we developed a core-shelled bioinspired low-density lipoprotein (bio-LDL) in which snail siRNA-loaded calcium phosphate nanoparticles were wrapped as the core and doxorubicin was embedded in the outer phospholipids modified with a synthetic peptide of apoB100 targeting LDL receptor-abundant tumor cells. Bio-LDL exhibited pH-responsive release, lysosomal escape ability, enhanced cytotoxicity and apoptotic induction. Bio-LDL could significantly inhibit the expression of snail and regulate EMT-related proteins to reduce tumor migration and invasion in vitro. Bio-LDL also displayed favorable tumor targeting and synergistic inhibition of tumor growth and metastasis in vivo. Therefore, the multifunctional bio-LDL will be a promising co-delivery vector and holds potential value for clinical translation.

Treatment response to eribulin and anlotinib in lung metastases from rare perianal adenoid cystic carcinoma: a case report.

Adenoid cystic carcinoma (ACC) is a rare salivary glands tumor and often displays aggressive behavior with frequent relapse and metastasis. The terminal ACC lacks standard treatment guidelines and is always accompanied by poor prognosis. Here, we report a case of rare perianal ACC who received resection and palliative adjuvant radiation. Five years later, PET-computed tomography (CT) showed perianal recurrence and multiple pulmonary metastases. Combined chemotherapy with doxorubicin, carboplatin and cyclophosphamide was applied for two cycles but ineffective. Further next-generation sequencing analysis of perianal tissue demonstrated the v-myb avian myelobastosis viral oncogene homolog and nuclear factor I/B fusion gene and two novel BCL-6 corepressor (BCOR) mutations (p.F1106Tfs*5 and p.L1524Hfs*8). The therapy was switched to eribulin and anlotinib and has been performed for eight cycles. At recent follow-ups, MRI and CT examinations revealed the diminishing perianal and pulmonary lesions. This study presented the first case of perianal ACC with multiple pulmonary metastases and particular BCOR mutations, who presented a durable response to eribulin and anlotinib, providing a potential therapeutic option for advanced refractory ACC.

Inosine Triphosphate Pyrophosphatase and NUDT15 are Good Predictors of Clinical Outcomes in Thiopurine-Treated Chinese Patients with Inflammatory Bowel Disease.

BACKGROUND: Although the relationship between NUDT15 and thiopurine-induced leukopenia has been proven in previous studies, no prominent factors explaining interindividual variations in its active metabolite, 6-thioguanine nucleotide (6-TGN), and clinical efficacy have been identified. In this study, the correlation between genotypes (thiopurine S-methyltransferase, NUDT15, and ITPA polymorphisms), 6-TGN concentrations, and clinical outcomes (efficacy and side effects) in patients with inflammatory bowel disease were investigated. METHODS: In total, 160 patients with inflammatory bowel disease were included, and the 3 genotyped genes and 6-TGN levels were measured by high-performance liquid chromatography. Statistical analyses and calculations were performed to determine their relationships. RESULTS: ITPA genotypes and 6-TGN concentration were both associated with the clinical effectiveness of azathioprine (P = 0.036 and P = 4.6 × 10-7), with a significant correlation also detected between them (P = 0.042). Patients with ITPA variant alleles exhibited higher 6-TGN levels than those with the wild-type allele. In addition, the relationship between NUDT15 and leukopenia and neutropenia was confirmed (P = 1.79 × 10-7 and 0.002). CONCLUSIONS: In summary, it is recommended that both ITPA and NUDT15 genotyping should be performed before azathioprine initiation. Moreover, the 6-TGN concentration should be routinely monitored during the later period of treatment.

Distribution evaluation of tacrolimus in the ascitic fluid of liver transplant recipients with liver cirrhosis by a sensitive ultra-performance liquid chromatography-tandem mass spectrometry method.

Tacrolimus has a narrow therapeutic index and large individual differences in pharmacokinetics. The distribution of tacrolimus in ascitic fluid and its influence on whole-blood tacrolimus were unclear. In this study, a sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was established and validated for the quantification of tacrolimus in the ascitic fluid of liver transplant recipients. Chromatographic separation was achieved on an Agilent ZORBAX Eclipse Plus Phenyl-Hexyl column (2.1 × 100 mm, 3.5 µm). Mass spectrometry was performed in multiple reaction monitoring conditions of transitions m/z 821.4→768.5 for tacrolimus. The concentrations of tacrolimus in the ascitic fluid range from 0.2 to 3.0 ng/mL, accounting for 1.19-31.87% of whole-blood tacrolimus concentrations. A linear mixed model showed a statistically significant positive correlation between the steady-state trough blood concentration of tacrolimus and the corresponding amount of tacrolimus excreted in the ascitic fluid for 24 consecutive hours, especially after normalization by daily dose per unit body weight. These data suggested that the distribution of tacrolimus in the ascitic fluid has great individual differences. The whole-blood tacrolimus concentration, dose per unit body weight, and other confounding factors may contribute to the excretion of tacrolimus in ascitic fluid, but the influence of tacrolimus excretion in drained ascitic fluid on the whole-blood tacrolimus concentration is negligible.

Population pharmacokinetics and dosage optimisation of tacrolimus coadministration with Wuzhi capsule in adult liver transplant patients.

This study aimed to establish a population pharmacokinetic model of tacrolimus coadministration with Wuzhi capsule and optimise the dosage regimen in adult liver transplant patients.Totally 1327 tacrolimus trough concentrations from 116 adult liver transplant patients were obtained for model development. A one-compartment model with first-order absorption and elimination was used to analyse the data, and the final model was internally verified using a goodness-of-fit diagnostic plot, bootstrap methods, and visual prediction test. A total of 29 patients with 250 tacrolimus trough concentrations were used for external validation via prediction-based diagnostics. Additionally, the simulation was used to optimise the recommended dose of tacrolimus and Wuzhi capsules.The estimated apparent clearance and volume of the distribution of tacrolimus were 15.4 L/h and 1210 L, respectively. The tacrolimus daily dose, Wuzhi capsule daily dose, postoperative time, alanine transaminase, haemoglobin, total bilirubin, direct bilirubin, estimated glomerular filtration rate, and urea, concomitant with voriconazole and fluconazole, were identified as significant covariates affecting the pharmacokinetic parameters. Internal and external validation showed that the final model was stable and reliable for predicting performance.The final model could provide guidance for dosage optimisation of tacrolimus coadministered with Wuzhi capsules in adult liver transplantation patients.

Cerebrospinal fluid metabolic profiling reveals divergent modulation of pentose phosphate pathway by midazolam, propofol and dexmedetomidine in patients with subarachnoid hemorrhage: a cohort study.

BACKGROUND: Agitation is common in subarachnoid hemorrhage (SAH), and sedation with midazolam, propofol and dexmedetomidine is essential in agitation management. Previous research shows the tendency of dexmedetomidine and propofol in improving long-term outcome of SAH patients, whereas midazolam might be detrimental. Brain metabolism derangement after SAH might be interfered by sedatives. However, how sedatives work and whether the drugs interfere with patient outcome by altering cerebral metabolism is unclear, and the comprehensive view of how sedatives regulate brain metabolism remains to be elucidated. METHODS: For cerebrospinal fluid (CSF) and extracellular space of the brain exchange instantly, we performed a cohort study, applying CSF of SAH patients utilizing different sedatives or no sedation to metabolomics. Baseline CSF metabolome was corrected by selecting patients of the same SAH and agitation severity. CSF components were analyzed to identify the most affected metabolic pathways and sensitive biomarkers of each sedative. Markers might represent the outcome of the patients were also investigated. RESULTS: Pentose phosphate pathway was the most significantly interfered (upregulated) pathway in midazolam (p = 0.0000107, impact = 0.35348) and propofol (p = 0.00000000000746, impact = 0.41604) groups. On the contrary, dexmedetomidine decreased levels of sedoheptulose 7-phosphate (p = 0.002) and NADP (p = 0.024), and NADP is the key metabolite and regulator in pentose phosphate pathway. Midazolam additionally augmented purine synthesis (p = 0.00175, impact = 0.13481) and propofol enhanced pyrimidine synthesis (p = 0.000203, impact = 0.20046), whereas dexmedetomidine weakened pyrimidine synthesis (p = 0.000000000594, impact = 0.24922). Reduced guanosine diphosphate (AUC of ROC 0.857, 95%CI 0.617-1, p = 0.00506) was the significant CSF biomarker for midazolam, and uridine diphosphate glucose (AUC of ROC 0.877, 95%CI 0.631-1, p = 0.00980) for propofol, and succinyl-CoA (AUC of ROC 0.923, 95%CI 0.785-1, p = 0.000810) plus adenosine triphosphate (AUC of ROC 0.908, 95%CI 0.6921, p = 0.00315) for dexmedetomidine. Down-regulated CSF succinyl-CoA was also associated with favorable outcome (AUC of ROC 0.708, 95% CI: 0.524-0.865, p = 0.029333). CONCLUSION: Pentose phosphate pathway was a crucial target for sedatives which alter brain metabolism. Midazolam and propofol enhanced the pentose phosphate pathway and nucleotide synthesis in poor-grade SAH patients, as presented in the CSF. The situation of dexmedetomidine was the opposite. The divergent modulation of cerebral metabolism might further explain sedative pharmacology and how sedatives affect the outcome of SAH patients.

Effectiveness and safety of path-based analgesic regimens designed by clinical pharmacists based on the type of biliary and pancreatic surgery.

WHAT IS KNOWN AND OBJECTIVE: As the incidence of postoperative pain in patients with biliary and pancreatic diseases has gradually increased, how to control postoperative pain has received increasing research attention. By reading pain management guidelines and multidisciplinary communication and cooperation, clinical pharmacists designed multi-mode analgesia regimens based on surgical types, in order to provide strong evidence for the effectiveness and safety of postoperative analgesia regimens and better serve patients. METHODS: Data from biliary or pancreatic surgery performed at Nanjing Drum Tower Hospital from 2019 to 2021 were collected. Take October 2020 as the time point to compare the outcomes before and after the implementation of the path-based postoperative analgesic regimens. The primary outcomes were NRS pain scores, sleep quality, and incidence of adverse reactions. Length of stay was a secondary outcome. RESULTS AND DISCUSSION: A total of 268 and 239 patients were enrolled in the study and control groups, respectively. Four path-based postoperative analgesic management regimens significantly reduced patients' static and dynamic NRS scores in the 24 h (p < 0.05). The patients' sleep quality were better than controls (p > 0.05). The incidence of adverse reactions and the length of stay in the study group were numerically lower than controls. Moderate analysis indicated that four analgesia regimens are more precise and better meet actual clinical needs. WHAT IS NEW AND CONCLUSION: Effective and safe postoperative pain management is particularly important for clinical purposes. Path-based postoperative analgesia regimens based on different types of surgery overcome the disadvantages of overly broad and generalized traditional guidelines, which play an important role in providing personalized and precise clinical services. Further, study findings provide evidence that four path-based analgesic regimens can reduce postoperative pain and reduce the length of hospital stay, which may provide a better direction for clinical postoperative pain management.

Sensitive colorimetric sensing of glutathione and H2O2 based on enhanced peroxidase mimetic activity of MXene@Fe3O4.

The peroxidase-like activity of MXene@Fe3O4 nanocomposites and the relevant colorimetric application have been investigated for the first time. According to a kinetic study, MXene@Fe3O4 nanocomposites displayed higher peroxidase activity than their individual components, and the catalytic process followed a ping-pong mechanism. The improved peroxidase-like activity of the MXene@Fe3O4 nanocomposites was obtained due to the synergetic impact of the Fe3O4 and MXene phases, the huge ion-accessible interface, and quick electron transfer channels in the nanocomposites. In the presence of hydrogen peroxide (H2O2), the MXene@Fe3O4 nanocomposites can catalyze the reaction of the colorless substrate 3, 3, 5, 5-tetramethylbenzidine (TMB) into oxidized TMB which revealed a blue color at 652 nm. After the introduction of glutathione (GSH), the blue color was gradually fading owing to the hydroxyl radical scavenging effect of glutathione. A colorimetric detection platform based on the peroxidase-like activity of the MXene@Fe3O4 nanocomposites was developed for H2O2 and GSH with a detection limit of 0.4 µM and 0.5 µM, respectively. The calibration plot for glutathione detection is calculated by absorbance difference at 652 nm, which ranged from 0.5 to 10 µM with a detection limit of 0.2 µM. The recoveries of GSH with different concentrations ranged from 93.76 to 108.50% and the relative standard deviation from 0.30 to 5.96%. This work significantly extends the application of MXene@Fe3O4 nanocomposites in the construction of colorimetric sensors and reveals a satisfactory result in real sample analysis.

A Metabolite Array Technology for Precision Medicine.

The application of metabolomics in translational research suffers from several technological bottlenecks, such as data reproducibility issues and the lack of standardization of sample profiling procedures. Here, we report an automated high-throughput metabolite array technology that can rapidly and quantitatively determine 324 metabolites including fatty acids, amino acids, organic acids, carbohydrates, and bile acids. Metabolite identification and quantification is achieved using the Targeted Metabolome Batch Quantification (TMBQ) software, the first cross-vendor data processing pipeline. A test of this metabolite array was performed by analyzing serum samples from patients with chronic liver disease (N = 1234). With high detection efficiency and sensitivity in serum, urine, feces, cell lysates, and liver tissue samples and suitable for different mass spectrometry systems, this metabolite array technology holds great potential for biomarker discovery and high throughput clinical testing. Additionally, data generated from such standardized procedures can be used to generate a clinical metabolomics database suitable for precision medicine in next-generation healthcare.

Developing a physiologically based pharmacokinetic model of apixaban to predict scenarios of drug-drug interactions, renal impairment and paediatric populations.

AIMS: To develop a physiologically based pharmacokinetic (PBPK) model for apixaban, an oral anticoagulant with a narrow therapeutic index, and to predict PK profiles and potential drug-drug interactions (DDIs) in patients with renal impairment and paediatrics. METHODS: A whole-body apixaban PBPK model was developed and validated in SimCYP for healthy adults with or without interacting drugs. The model was extended to renal impairment and paediatrics. Observed PK data in adults were compared with predicted data. The effect of renal function, age and DDIs on apixaban PK was investigated. RESULTS: The PBPK model successfully predicted the PK of apixaban alone and under the influence of interacting drugs. For patients with renal impairment, the PBPK model successfully predicted the fold change in each impairment group; inhibitory DDI and renal impairment had a synergistic effect on the increase of apixaban exposure (e.g., almost 3-fold increase of AUC in ketoconazole + severe renal impairment group). For infants younger than 1 year, the exposure of apixaban decreased with increased weight-normalized clearance. For newborn infants, AUC of apixaban was >2-fold higher than that in children older than 1 year. Meanwhile, the effect of DDI seems to be weakened while the effect of renal impairment might be enhanced in infants younger than 1 year. CONCLUSION: Our study provides a reasonable approach to estimate the dose adjustment for the first use of apixaban in special populations with complex situations, which has the opportunity to make the clinical practice much safer.

Daphnetin Ameliorates Experimental Autoimmune Encephalomyelitis Through Regulating Heme Oxygenase-1.

To assess the potential role of daphnetin, a clinically used anti-inflammatory agent, on the development of the inflammatory and neurodegenerative disease, we investigated its immune regulatory function in a murine model of experimental autoimmune encephalomyelitis (EAE). Significantly, lower levels of pro-inflammatory cytokines including interleukin (IL)-17, interferon-γ, Il6, Il12a, and Il23a were observed in brains of daphnetin-treated EAE mice, compared with those in control littermates. We also confirmed that daphnetin suppressed the production of IL-1ß, IL-6, and tumor necrosis factor-α in lipopolysaccharide-stimulated mouse BV2 microglial cells. Mechanistically, heme oxygenase-1 (HO-1), a canonical anti-oxidant and anti-inflammatory factor, was found to be substantially induced by daphnetin treatment in BV2 cells. Also, a significantly higher level of HO-1, accompanied by a decreased level of malondialdehyde, was observed in daphnetin-treated EAE mice. More importantly, the deletion of HO-1 in BV2 microglia largely abrogated daphnetin-mediated inhibition of the inflammatory response. Together, our data demonstrate that daphnetin has an anti-inflammatory and neuroprotective role during the pathogenesis of EAE, which is partially at least, dependent on its regulation of HO-1.

Drug-drug interaction extraction via hybrid neural networks on biomedical literature.

Adverse events caused by drug-drug interaction (DDI) not only pose a serious threat to health, but also increase additional medical care expenditure. However, despite the emergence of many excellent text mining-based DDI classification methods, achieving a balance between using simpler method and better model performance is still unsatisfactory. In this article, we present a deep learning method of stacked bidirectional Gated Recurrent Unit (GRU)- convolutional neural network (SGRU-CNN) model which apply stacked bidirectional GRU (BiGRU) network and convolutional neural network (CNN) on lexical information and entity position information respectively to conduct DDIs extraction task. Furthermore, SGRU-CNN model assigns the weights of each word feature to improve performance with one attentive pooling layer. On the condition that other values are not inferior to other algorithms, experimental results on the DDI Extraction 2013 corpus show that our model achieves a 1.54% improvement in recall value. And the proposed SGRU-CNN model reaches great performance (F1-score: 0.75) with the fewest features, indicating an excellent balance between avoiding redundant preprocessing task and higher accuracy in relation extraction on biomedical literature using our method.