DataSheet_1_Integrative Analysis of Pharmacokinetic and Metabolomic Profiles for Predicting Metabolic Phenotype and Drug Exposure Caused by Sotorasib in Rats.pdf

Sotorasib is a novel targeted inhibitor of Kirsten rat sarcoma (KRAS) (G12C) that has shown exciting tumor-suppressing effects not only for single targeted agents but also for combination with immune checkpoint inhibitors. However, no integrative analysis of the pharmacokinetics (PK) and pharmacometabolomics (PM) of sotorasib has been reported to date. In the present study, a sensitive and robust high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method was firstly developed and fully validated for the quantitation of sotorasib in rat plasma. After one-step protein precipitation, sotorasib and an internal standard (carbamazepine) were separated on a Waters XBrige C18 column (50 mm × 2.1 mm, 3.5 μm) and analyzed in electrospray ionization positive ion (ESI+) mode. The optimized method was fully validated according to guidance and was successfully applied for the PK study of sotorasib at a dose of 10 mg/kg. In addition, a longitudinal and transversal PM was employed and correlated with PK using partial least squares model and Pearson’s analysis. With multivariate statistical analysis, the selected six (AUC model) and nine (Cmax model) metabolites completely distinguished the high- and low-exposure groups after sotorasib treatment, which indicates that these potential biomarkers can predict drug exposure or toxicity. The results of this study will not only shed light on how sotorasib disturbs the metabolic profiles and the relationship between PK and PM but also offer meaningful references for precision therapy in patients with the KRAS (G12C) mutation.</p

Dual Responsive Supramolecular Hydrogel with Electrochemical Activity

Supramolecular materials with reversible responsiveness to environmental changes are of particular research interest in recent years. Inclusion complexation between cyclodextrin (CD) and ferrocene (Fc) is well-known and extensively studied because of its reversible association–dissociation controlled by the redox state of Fc. Although there are quite a few reported nanoscale materials incorporating this host–guest pair, polymeric hydrogels with electrochemical activity based on this interactive pair are still rare. Taking advantage of our previous reported hybrid inclusion complex (HIC) hydrogel structure, a new Fc–HIC was designed and obtained with β-CD-modified quantum dots as the core and Fc-ended diblock co-polymer p(DMA-b-NIPAM) as the shell, to achieve an electrochemically active hydrogel at elevated temperatures. Considering the two independent cross-linking strategies in the network structure, i.e., the interchain aggregation of pNIPAM and inclusion complexation between CD and Fc on the surface of the quantum dots, the hydrogel was fully thermo-reversible and its gel–sol transition was achieved after the addition of either an oxidizing agent or a competitive guest to Fc

sj-docx-1-cat-10.1177_10760296221130334 - Supplemental material for Disease Burden in Patients with von Willebrand Disease Potentially Eligible for Prophylaxis: Post Hoc Analysis of a European Cross-Sectional Study

Supplemental material, sj-docx-1-cat-10.1177_10760296221130334 for Disease Burden in Patients with von Willebrand Disease Potentially Eligible for Prophylaxis: Post Hoc Analysis of a European Cross-Sectional Study by Ping Du, George Morgan, Sarah Brighton and Shawn X. Sun in Clinical and Applied Thrombosis/Hemostasis</p

Effects of sirtuin 1 deficiency on trophoblasts and its implications in the pathogenesis of pre-eclampsia

Sirtuin 1 (SIRT1) is mainly localised in syncytiotrophoblasts and cytotrophoblasts, and is involved in pregnancy regulation. However, data on the association between SIRT1 and pre-eclampsia (PE) remains limited. This study aimed to investigate the role of SIRT1 in PE pathophysiology. Placental SIRT1 expression, as well as serum SIRT1, placental growth factor (PlGF), and soluble FMS-like tyrosine kinase 1 (sFlt-1) levels, were measured using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assays in 40 healthy pregnant women (NP group) and 40 women with severe PE (PE group). Additionally, the effects of SIRT1 on the migration, invasion, PlGF, and sFlt-1 secretion of HTR-8/SVneo cells were analysed. SIRT1 expression was significantly reduced in the placenta of patients with severe PE compared with that in healthy pregnant women. Compared with the NP group, serum SIRT1 and PlGF expression was significantly lower in the PE group; however, the expression of serum sFlt-1 was significantly higher in the PE group. Correlation analysis showed that in the PE group, placental SIRT1 protein levels positively correlated with serum PlGF levels (r = 0.468, P = .002) and negatively correlated with serum sFlt-1 levels (r = −0.542, P  SIRT1 deficiency may contribute to the pathogenesis of pre-eclampsia by reducing trophoblastic migration, invasion, and PlGF secretion and increasing sFlt-1 secretion. Pre-eclampsia is a serious obstetric disorder that begins in the placenta and can occur midway through pregnancy. However, its exact disease process remains unknown. During early pregnancy, trophoblasts (cells that differentiate from fertilised eggs) evolve into new blood vessels that supply oxygen and nutrients to the placenta and maintain placental formation. In people with pre-eclampsia, problematic trophoblasts lead to abnormal placental formation and release of sFlt-1 and PlGF into the mother’s blood, damaging blood vessels. Experts reported that the intracellular enzyme SIRT1 might be associated with developing pre-eclampsia. SIRT1 expression in the placenta of pregnant women with pre-eclampsia was lower than normal, and the decrease in SIRT1 levels in HTR-8/Svneo trophoblasts prevented their ability to form blood vessels and altered sFlt-1 and PlGF secretion. Hence, our findings suggest that reduced SIRT1 in trophoblasts may lead to pre-eclampsia by affecting their ability to form placental blood vessels and altering enzyme secretion.</p

The basic physical and chemical parameters of the overlying water of the Jiaojiang Estuary.

<p>The basic physical and chemical parameters of the overlying water of the Jiaojiang Estuary.</p

DataSheet_1_Serum Eicosanoids Metabolomics Profile in a Mouse Model of Renal Cell Carcinoma: Predicting the Antitumor Efficacy of Anlotinib.docx

Anlotinib (ANL) shows promising efficacy in patients with renal cell cancer (RCC). Here, for the first time, a serum eicosanoid metabolomics profile and pharmacodynamics in Renca syngeneic mice treated with ANL was performed and integrated using our previous HPLC-MS/MS method and multivariate statistical analysis. The tumor growth inhibition rates of ANL were 39% and 52% at low (3 mg/kg) and high (6 mg/kg) dose levels, without obvious toxicity. A total of 15 disturbed metabolites were observed between the normal group and the model group, and the intrinsic metabolic phenotype alterations had occurred due to the treatment of ANL. A total of eight potential metabolites from the refined partial least squares (PLS) model were considered as potential predictive biomarkers for the efficacy of ANL, and the DHA held the most outstanding sensitivity and specificity with an area under the receiver operating characteristic curve of 0.88. Collectively, the results of this exploratory study not only provide a powerful reference for understanding eicosanoid metabolic reprogramming of ANL but also offer an innovative perspective for the development of therapeutic targets and strategies, the discovery of predictive biomarkers, and the determination of effective tumor monitoring approaches.</p

DataSheet1_Integration Analysis of Pharmacokinetics and Metabolomics to Predict Metabolic Phenotype and Drug Exposure of Remdesivir.docx

Remdesivir has displayed pharmacological activity against SARS-CoV-2. However, no pharmacometabolomics (PM) or correlation analysis with pharmacokinetics (PK) was revealed. Rats were intravenously administered remdesivir, and a series of blood samples were collected before and after treatment. Comprehensive metabolomics profile and PK were investigated and quantitated simultaneously using our previous reliable HPLC-MS/MS method. Both longitudinal and transversal metabolic analyses were conducted, and the correlation between PM and PK parameters was evaluated using Pearson’s correlation analysis and the PLS model. Multivariate statistical analysis was employed for discovering candidate biomarkers which predicted drug exposure or toxicity of remdesivir. The prominent metabolic profile variation was observed between pre- and posttreatment, and significant changes were found in 65 metabolites. A total of 15 metabolites—12 carnitines, one N-acetyl-D-glucosamine, one allantoin, and one corticosterone—were significantly correlated with the concentration of Nuc (active metabolite of remdesivir). Adenosine, spermine, guanosine, sn-glycero-3-phosphocholine, and l-homoserine may be considered potential biomarkers for predicting drug exposure or toxicity. This study is the first attempt to apply PM and PK to study remdesivir response/toxicity, and the identified candidate biomarkers might be used to predict the AUC and Cmax, indicating capability of discriminating good or poor responders. Currently, this study originally offers considerable evidence to metabolite reprogramming of remdesivir and sheds light on precision therapy development in fighting COVID-19.</p

Effect of comb polymer dispersants with different molecular structures on the performance of LiFePO₄ suspensions

A series of comb polymers poly(2-(dimethylamino)ethyl methacrylate (DMAEMA)-co-methacrylic acid (MAA)-co-methoxy polyethylene glycol methacrylate (MPEGMA)) (poly(DMAEMA-MAA-MPEGMA, DMM) were synthesized and used as N-methyl-2-pyrolidinone (NMP)-based lithium iron phosphate (LFP) suspension dispersants. The effects of the grafting density of the carboxyl group as the anchoring group and the chain length of the side chain of PEG, which plays the role of spatial site resistance, on the rheological properties and suspension stability of the slurry were systematically investigated. By investigating the adsorption amount and thickness of DMM on the LFP surface, combined with calculations based on the scalar law and Flory theory, the molecular structure of the comb polymer dispersant was revealed to influence the adsorption and dispersion performance. The dispersion of LiFePO4 was due to the synergistic effects of adsorption and steric hindrance effect, which resulted that dispersants with medium carboxyl density and PEG side chain length can improve the dispersion performance and stability.</p

Additional file 1 of Transcriptome sequencing reveals core regulation modules and gene signatures of Zusanli acupoints in response to different moxibustion warm stimulation in adjuvant arthritis rat

Additional file 1 Supplementary Table 1. Quality preprocessing of transcriptome sequencing data

PCA ordination diagram of the anammox communities calculated using 16S rRNA gene sequences from Jiaojiang estuarine sediments.

<p>PCA ordination diagram of the anammox communities calculated using 16S rRNA gene sequences from Jiaojiang estuarine sediments.</p