A phase I study of ridaforolimus in adult Chinese patients with advanced solid tumors

PURPOSE: Ridaforolimus (AP23573, MK-8669 or deforolimus) is an inhibitor of mammalian target of rapamycin (mTOR), an important regulator in the cell survival pathway. This open-label, single center phase I study aimed to investigate the pharmacokinetic (PK) and safety profiles of ridaforolimus in Chinese patients with treatment-refractory advanced or relapsed solid tumors. The PK data generated from these Chinese patients were further compared with those previously reported in Caucasian and Japanese patient populations. EXPERIMENTAL DESIGN: The patients were given an oral dose of 40 mg of ridaforolimus on Day 1 of the study. On Day 8, patients were initiated on a treatment regimen that comprised a once daily dose of 40 mg of ridaforolimus for five consecutive days, followed by a 2-day off-drug interval. Patients repeated this regimen until disease progression or intolerance. Blood samples were collected at specific times pre- and post-treatment to establish the PK profile of ridaforolimus in all patients. RESULTS: Fifteen patients were given at least one dose of 40 mg of ridaforolimus. The median absorption lag-time was 2 hours, the median T(max) was 4 hours and the mean elimination half-life was 53 hours. The accumulation ratio for AUC(0-24hr) was 1.3 on day 19 (steady state)/day 1 (after a single dose). The most common drug-related adverse events (AEs) that occurred in ≥40% of patients were stomatitis, proteinuria, leukopenia, hyperglycemia, and pyrexia. Grade 3/4 drug-related AEs were anemia, stomatitis, fatigue, thrombocytopenia, constipation, gamma glutamyltransferase increase, and proteinuria. All 11 evaluable patients achieved stable disease. CONCLUSIONS: Oral ridaforolimus at a daily dose of 40 mg were generally well tolerated in Chinese patients with advanced or refractory solid tumors. Adverse events and PK profiles of ridaforolimus in this study were similar to those from Caucasian and Japanese patients reported previously

A Novel Cationic Lignin-amine Emulsifier with High Performance Reinforced via Phenolation and Mannich Reactions

A novel cationic lignin-amine emulsifier with high surface activity was prepared from kraft lignin (KL) via the phenolation of KL to obtain phenolated kraft lignin (PKL) and improve reaction sites. The introduction of dehydroabietyl groups as hydrophobic groups and diethylenetriamino groups as hydrophilic groups in PKL, by Mannich reactions, enhanced the performance of the emulsifier. The results showed that the number of the hydroxyphenyl groups in PKL was 0.27/C9 unit when 1 mol lignin was treated with 10 mol phenol at 60 °C for 6 h under 60 wt% sulfuric acid. The numbers of dehydroabietyl groups and diethylenetriamino groups in PKL were 0.18/C9 and 0.13/C9 unit, respectively. The surface tension of the emulsifier was 30.03 mN·m-1 at a concentration of 0.03 M hydrochloric acid aqueous solution with a pH 2.0, which is close to the commercial surfactant cetyltrimethylammonium bromide (CTAB). The zeta potential of the emulsifier was 45.1 mV, and its emulsifiability was 72 min. In contrast, the surface tension of the emulsifier prepared by non-phenolated lignin at the same condition was 38.67 mN·m-1, where the maximum zeta potential was 40.03 mV and its emulsifiability was 53 min. As expected, the performance of the emulsifier was reinforced by the phenolation reaction

Identification of Signature Genes in the PD-1 Relative Gastric Cancer Using a Combined Analysis of Gene Expression and Methylation Data

Background. The morbidity and mortality rates for gastric cancer (GC) rank second among all cancers, indicating the serious threat it poses to human health, as well as human life. This study aims to identify the pathways and genes as well as investigate the molecular mechanisms of tumor-related genes in gastric cancer (GC). Method. We compared differentially expressed genes (DEGs) and differentially methylated genes (DMGs) in gastric cancer and normal tissue samples using The Cancer Genome Atlas (TCGA) data. The Kyoto Encyclopedia of Gene and Genome (KEGG) and the Gene Ontology (GO) enrichment analysis’ pathway annotations were conducted on DMGs and DEGs using a clusterProfiler R package to identify the important functions, as well as the biological processes and pathways involved. The intersection of the two was chosen and defined as differentially methylated and expressed genes (DMEGs). For DMEGs, we used the principal component analysis (PCA) to differentiate gastric cancer from adjacent samples. The linear discriminant analysis method was applied to categorize the samples using DMEGs methylation data and DMEGs expression profiles data and was validated using the leave-one-out cross-validation (LOOCV) method. We plotted the ROC curve for the classification and calculated the AUC (area under the ROC curve) value for a more intuitive view of the classification effect. We also used the NetworkAnalyst 3.0 tool to analyze DMEGs, using DrugBank to acquire information on protein-drug interactions and generate a network map of gene-drug interactions. Results. We identified a total of 971 DMGs in 188 PD-1 negative and 187 PD-1 positive gastric cancer samples obtained from TCGA. The KEGG and GO enrichment analysis showed the involvement of the regulation of ion transmembrane transport, collagen-containing extracellular matrix, cell-cell junction, and peptidase regulator activity. We simultaneously obtained 1,189 DEGs, out of which 986 were downregulated, while 203 were upregulated in tumors. The enriched analysis of the GO’s and KEGG’s pathways indicated that the most significant pathways included an intestinal immune network for IgA production, Staphylococcus aureus infection, cytokine-cytokine receptor interaction, and viral protein interaction with cytokine and cytokine receptor, which have previously been linked with gastric cancer. The compound DB01830 can bind well to the active site of the LCK protein and shows good stability, thus making it a potential inhibitor of the LCK protein. To observe the relationship between DMEGs’ expression and prognosis, we observed 10 genes, among which were TRIM29, TSPAN8, EOMES, PPP1R16B, SELL, PCED1B, IYD, JPH1, CEACAM5, and RP11-44K6.2. Their high expressions were related to high risks. Besides, those genes were validated in different internal and external validation sets. Conclusion. These results may provide potential molecular biological therapy for PD-1 negative gastric cancer

Near Real-Time 3D Reconstruction and Quality 3D Point Cloud for Time-Critical Construction Monitoring

Improving the rapidity of 3D reconstruction is vital for time-critical construction tasks such as progress monitoring and hazard detection, but the majority of construction studies in this area have focused on improving its quality. We applied a Direct Sparse Odometry with Loop Closure (LDSO)-based 3D reconstruction method, improving the existing algorithm and tuning its hyper-parameter settings, to achieve both near real-time operation and quality 3D point cloud simultaneously. When validated using a benchmark dataset, the proposed method showed notable improvement in 3D point cloud density, as well as loop closure robustness, compared to the original LDSO. In addition, we conducted a real field test to validate the tuned LDSO’s accuracy and speed at both object and site scales, where we demonstrated our method’s near real-time operation and capability to produce a quality 3D point cloud comparable to that of the existing method. The proposed method improves the accessibility of the 3D reconstruction technique, which in turn helps construction professionals monitor their jobsite safety and progress in a more efficient manner

Centrality-based pathway enrichment: a systematic approach for finding significant pathways dominated by key genes

<p>Abstract</p> <p>Background</p> <p>Biological pathways are important for understanding biological mechanisms. Thus, finding important pathways that underlie biological problems helps researchers to focus on the most relevant sets of genes. Pathways resemble networks with complicated structures, but most of the existing pathway enrichment tools ignore topological information embedded within pathways, which limits their applicability.</p> <p>Results</p> <p>A systematic and extensible pathway enrichment method in which nodes are weighted by network centrality was proposed. We demonstrate how choice of pathway structure and centrality measurement, as well as the presence of key genes, affects pathway significance. We emphasize two improvements of our method over current methods. First, allowing for the diversity of genes’ characters and the difficulty of covering gene importance from all aspects, we set centrality as an optional parameter in the model. Second, nodes rather than genes form the basic unit of pathways, such that one node can be composed of several genes and one gene may reside in different nodes. By comparing our methodology to the original enrichment method using both simulation data and real-world data, we demonstrate the efficacy of our method in finding new pathways from biological perspective.</p> <p>Conclusions</p> <p>Our method can benefit the systematic analysis of biological pathways and help to extract more meaningful information from gene expression data. The algorithm has been implemented as an R package CePa, and also a web-based version of CePa is provided.</p

Enhancement of fermentable sugar yield by competitive adsorption of non-enzymatic substances from yeast and cellulase on lignin

Background: Enhancement of enzymatic digestibility by some supplementations could reduce enzyme loading and cost, which is still too high to realize economical production of lignocellulosic biofuels. A recent study indicates that yeast hydrolysates (YH) have improved the efficiency of cellulases on digestibility of furfural residues (FR). In the current work, the components of YH were separated by centrifugation and size exclusion chromatography and finally characterized in order to better understand this positive effect. Results: A 60.8% of nitrogen of yeast cells was remained in the slurry (YHS) after hydrothermal treatment. In the supernatant of YH (YHL), substances of high molecular weight were identified as proteins and other UV-absorbing compounds, which showed close molecular weight to components of cellulases. Those substances attributed to a synergetic positive effect on enzymatic hydrolysis of FR. The fraction of YHL ranged from 1.19 to 2.19 mL (elution volume) contained over 50% of proteins in YHL and had the best performance in stimulating the release of glucose. Experiment results proved the adsorption of proteins in YHL on lignin. Conclusions: Supplementation of cellulases with YH enhances enzymatic digestibility of FR mainly by a competitive adsorption of non-enzymatic substances on lignin. The molecular weight of these substances has a significant impact on their performance. Different strategies can be used for a good utilization of yeast cells in terms of biorefinery concept