An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with an extremely low 5-year survival rate. Accumulating evidence has unveiled that inflammatory response promotes tumor progression, enhances angiogenesis, and causes local immunosuppression. Herein, we aim to develop an inflammatory related prognostic signature, and found it could be used to predict gemcitabine response in PDAC. Methods: PDAC cohorts with mRNA expression profiles and clinical information were systematically collected from the four public databases. An inflammatory response related genes (IRRGs) prognostic signature was constructed by LASSO regression analysis. Kaplan-Meier survival analysis, receiver operating characteristic analysis, principal component analysis, and univariate and multivariate Cox analyses were carried out to evaluate effectiveness, and reliability of the signature. The correlation between gemcitabine response and risk score was evaluated in the TCGA-PAAD cohort. The GDSC database, pRRophetic algorithm, and connectivity map analysis were used to predict gemcitabine sensitivity and identify potential drugs for the treatment of PDAC. Finally, we analyzed differences in frequencies of gene mutations, infiltration of immune cells, as well as biological functions between different subgroups divided by the prognostic signature. Results: We established a seven IRRGs (ADM, DCBLD2, EREG, ITGA5, MIF, TREM1, and BTG2) signature which divided the PDAC patients into low- and high-risk groups. Prognostic value of the signature was validated in 11 PDAC cohorts consisting of 1337 PDAC patients from 6 countries. A nomogram that integrated the IRRGs signature and clinicopathologic factors of PDAC patients was constructed. The risk score showed positive correlation with gemcitabine resistance. Two drugs (BMS-536924 and dasatinib) might have potential therapeutic implications in high-risk PDAC patients. We found that the high-risk group had higher frequencies of KRAS, TP53, and CDKN2A mutations, increased infiltration of macrophages M0, neutrophils, and macrophages M2 cells, as well as upregulated hypoxia and glycolysis pathways, while the low-risk group had increased infiltration of CD8+ T, naïve B, and plasma and macrophages M1 cells. Conclusion: We constructed and validated an IRRGs signature that could be used to predict the prognosis and gemcitabine response of patients with PDAC, as well as two drugs (BMS-536924 and dasatinib) may contribute to PDAC treatment.

Comparing the efficacy of bag-valve mask, endotracheal intubation, and laryngeal mask airway for subjects with out-of-hospital cardiac arrest: an indirect meta-analysis.

BACKGROUND: For subjects with out-of-hospital cardiac arrest (OHCA), bag-valve mask (BVM), endotracheal intubation (ETI), and laryngeal mask airway (LMA) are the most common methods of ventilatory support; however, the best choice remains controversial. METHODS: A comprehensive search of online databases was performed. A traditional meta-analysis was performed to determine the risk ratio of BVM vs. LMA and ETI vs. LMA. Indirect treatment comparisons (ITCs) were conducted to compare BVM and ETI. RESULTS: A total of 13 full-text articles reporting the efficacy of BVM, ETI, and LMA were considered in this analysis. BVM and LMA had the same effect regarding return of spontaneous circulation (ROSC) (23% vs. 24%; RR =0.84), survival rate at admission (19% vs. 21%; RR =0.82) or discharge (6% vs. 4%; RR =0.61). ETI was superior to LMA in terms of ROSC (48% vs. 23%; RR =0.72) and survival rate at both admission (27% vs. 19%; RR =0.85) and discharge (12% vs. 4%; RR =0.90). BVM was inferior to ETI in terms of ROSC (24% vs. 48%; RR =0.86), survival to admission rate (21% vs. 27%; RR =1.037), and survival to discharge rate (6% vs. 12%; RR =1.476). CONCLUSIONS: ETI should be considered for airway management as early as possible, which can improve the subject's success rate of recovery and survival to admission rate. In future, large-scale, multi-center, randomized controlled studies should be conducted to evaluate the exact efficacy of BVM, ETI, and LMA for the first aid of subjects with OHCA.

Layer-by-layer nanoparticles co-loading gemcitabine and platinum (IV) prodrugs for synergistic combination therapy of lung cancer.

PURPOSE: Cisplatin plus gemcitabine (GEM) is a standard regimen for the first-line treatment of advanced non-small cell lung cancer. The aim of this study was to prepare biocompatible and biodegradable polymeric prodrugs and construct nanoparticles (NPs) with layer-by-layer (LbL) technique. METHODS: Platinum (Pt) (IV) complex with a carboxyl group was conjugated to the amino group of chitosan (CH), resulting in a CH-Pt conjugation with positive charge. GEM with amino group was conjugated to the carboxyl group of hyaluronic acid (HA), resulting in a HA-GEM conjugation with negative charge. Novel LbL NPs consisting of the CH-Pt core and the HA-GEM layer, named as HA-GEM/CH-Pt NPs, were constructed. The physicochemical properties of the HA-GEM/CH-Pt NPs were investigated. In vitro cytotoxicity against human non-small lung cancer cells (NCl-H460 cells) was investigated, and in vivo antitumor efficiency was evaluated on mice bearing NCl-H460 cells xenografts. RESULTS: HA-GEM/CH-Pt NPs have a size of about 187 nm, a zeta potential value of -21 mV and high drug encapsulation efficiency of 90%. The drug release of HA-GEM/CH-Pt NPs exhibited a sustained behavior. HA-GEM/CH-Pt NPs could significantly enhance in vitro cytotoxicity and in vivo antitumor effect against lung cancer animal model compared to the single-drug-loaded NPs and free drug solutions. CONCLUSION: The results demonstrated that the HA-GEM/CH-Pt NPs might be a promising system for the synergetic treatment of lung carcinoma.

Development and validation of a liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of dabigatran etexilate, intermediate metabolite and dabigatran in 50µL rat plasma and its application to pharmacokinetic study.

A simple, rapid and specific high performance liquid chromatography-electrospray ionization tandem mass spectrometry method was developed for simultaneous determination of dabigatran etexilate (BIBR 1048 MS), the intermediate metabolite (BIBR 1087 SE) and dabigatran (BIBR 953 ZW). In this method, a stacked protein precipitation with methanol was performed in Sirocco 96-well filtration plates to extract analytes using only 50µL plasma. The analysis was performed on an Ultimate TM XB-C18 (4.6×50mm, 5µm) column using gradient elution with a mobile phase composed of methanol containing 0.01% formic acid and pure water at a flow rate of 0.3mL/min. The gradient was set to 90% methanol containing 0.01% formic acid for the first 1.0min, after which it dropped to 10%, and then was kept at 10% for the next 5min followed by an additional 1.0min at the initial composition of 90% methanol containing 0.01% formic acid for equilibration. Detection was performed on a triple-quadrupole mass spectrometer electrospray ionization interface in positive ion mode. Linear calibration curves were obtained over the concentration ranges of 1-500ng/mL for all analytes. The validated LC-MS/MS method for its selectivity, sensitivity, linearity, precision, accuracy, recovery, matrix effect and stability had been successfully applied to a pharmacokinetic study of analytes in rat plasma following a single oral administration of 15mg/kg dabigatran etexilate.

Simultaneous determination of amlodipine and bisoprolol in rat plasma by a liquid chromatography/tandem mass spectrometry method and its application in pharmacokinetic study.

A sensitive, specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the quantitative determination of amlodipine and bisoprolol, using clenbuterol as the internal standard (IS). The analytes and IS were isolated from 100µL plasma samples by a simple liquid-liquid extraction (LLE). Reverse-phase high performance liquid chromatography (RP-HPLC) separation was accomplished on a Diamonsil C(18) column (50mm×4.6mm, 5µm) with a mobile phase composed of methanol-water-formic acid (75:25:0.01, v/v/v) at a flow rate of 0.3mL/min. The method had a chromatographic total run time of 3min. Multiple reacting monitoring (MRM) transitions of m/z [M+H](+) 409.1→237.9 (amlodipine), m/z [M+H](+) 326.2→116.0 (bisoprolol) and m/z [M+H](+) 277.0→203.0 (clenbuterol, IS) were used to quantify amlodipine, bisoprolol and IS, respectively. The method was sensitive with a lower limit of quantitation (LLOQ) of 0.2ng/mL for both amlodipine and bisoprolol, and the linear range was 0.2-50ng/mL for both amlodipine and bisoprolol (r(2)>0.9961). All the validation data, such as accuracy, precision and inter-day repeatability, were within the required limits. The method was successfully applied to pharmacokinetic studies of amlodipine and bisoprolol in Sprague-Dawley (SD) rats.