Simultaneous determination of ZL-01, a novel nucleotide prodrug, and its metabolites in rat plasma by LC-MS/MS: Application to pharmacokinetic study.

ZL-01 is a novel dual-prodrug which shows promise to be an antiviral candidate for hepatitis C virus. Here we have established a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of ZL-01 and its four metabolites (M1, M7, M8, and M9) in rat plasma with special consideration of ex vivo ZL-01, M1, and M7 stability. Several factors affecting the stability were investigated. EDTA and citric acid solution (1 M) were added to plasma to maintain the stability of analytes. The protein-precipitation method was selected with acetonitrile containing sofosbuvir as internal standard (IS). Adequate separation of ZL-01 and its metabolites was achieved on XSelect HSS T3 (3.5 µm, 4.6 × 150 mm) column by a gradient-elution with a mobile phase consisting of 0.1% formic acid and acetonitrile at a flow rate of 0.5 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 599.2→418.5 for ZL-01, m/z 529.7→398.2 for M1, m/z 330.5→182.0 for M7, m/z 260.3→112.1 for M8, m/z 261.3→113.2 for M9 and m/z 530.4→243.4 for IS. The calibration curves exhibited good linearity (r＞0.997) for all components. The lower limit of quantitation (LLOQ) was in the range of 1-2 ng/mL. The intra-day and inter-day precisions (RSD) at three different levels were both less than 10.2% and the accuracies (RE) ranged from -3.7-7.6%. The matrix effect and extraction recovery of them ranged from 84% to 110.3% and 88.3-106.3%. This LC-MS/MS method for the simultaneous quantitation of ZL-01 and its metabolites was developed successfully and applied in the pharmacokinetic studies of these in rats. Pharmacokinetic results indicated ZL-01 would be metabolized rapidly and M8 might be the main metabolites after oral absorption.

Oncogenic gene TRIM10 confers resistance to cisplatin in osteosarcoma cells and activates the NF-κB signaling pathway.

Deregulation of tripartite motif (TRIM) family proteins contribute to multiple biological processes such as neurodegeneration, development, inflammation, cell survival, apoptosis, and carcinogenesis. However, the biological function and molecular mechanism of TRIM family proteins in osteosarcoma chemoresistance remain unclear. In the current study, we found the protein expression of TRIM10 was markedly overexpressed in cisplatin resistance's osteosarcoma tissues and TRIM10 overexpression was inversely correlated with osteosarcoma patient survival. Furthermore, overexpression of TRIM10 confers cisplatin resistance on osteosarcoma cells; however, repressing TRIM10 sensitized osteosarcoma cell lines to cisplatin cytotoxicity in vitro. Mechanically, TRIM10 upregulated the nuclear levels of p65, thereby activating canonical NF-κB signaling. Taken together, our results suggest that TRIM10 contributed to cisplatin resistance in osteosarcoma cells, and targeting the TRIM10/p65 axis may represent a promising strategy to enhance cisplatin response in osteosarcoma patients with chemoresistance.

Validation of the Palliative Prognostic Index, Performance Status-Based Palliative Prognostic Index and Chinese Prognostic Scale in a home palliative care setting for patients with advanced cancer in China.

BACKGROUND: The predictive value of the prognostic tool for patients with advanced cancer is uncertain in mainland China, especially in the home-based palliative care (HPC) setting. This study aimed to compare the accuracy of the Palliative Prognostic Index (PPI), the Performance Status-Based Palliative Prognostic Index (PS-PPI), and the Chinese Prognosis Scale (ChPS) for patients with advanced cancer in the HPC setting in mainland China. METHODS: Patients with advanced cancer admitted to the hospice center of Yuebei People's Hospital between January 2014 and December 2018 were retrospectively calculated the scores according to the three prognostic tools. The Kaplan-Meier method was used to compare survival times among different risk groups. Receiver operating characteristic curve analysis was used to assess the predictive value. The accuracy of 21-, 42- and 90-day survival was compared among the three prognostic tools. RESULTS: A total of 1863 patients were included. Survival time among the risk groups of all prognostic tools was significantly different from each other except for the PPI. The AUROC of the ChPS was significantly higher than that of the PPI and PS-PPI for 7-, 14, 21-, 42-, 90-, 120-, 150- and 180-day survival (P < 0.05). The AUROC of the PPI and PS-PPI were not significantly different from each other (P > 0.05). CONCLUSIONS: The ChPS is more suitable than the PPI and PS-PPI for advanced cancer patients in the HPC setting. More researches are needed to verify the predictive value of the ChPS, PPI, and PS-PPI in the HPC setting in the future.

[Volume fraction of gas vesicle and floating characteristics of cyanobacteria in Taihu Lake under different pressures].

In order to ascertain the volumetric change of gas vesicles in cyanobacteria and the floating characteristics, capillary pressure method and image analysis method were used to study burst situation and remanent volume fraction of gas vesicles in cyanobacteria under different pressures. The reform situation after pressuring was also analyzed in this research. The results showed that the volume fraction of gas vesicles in Taihu Lake were 29.52%, 5.73%, 4.43%, 2.71%, 2.46%, 2.19% under 0 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa determined by the image analysis, and were 10.93%, 1.14%, 0.90%, 0.27%, 0.14%, 0.04% determined by the capillary pressure method; cyanobacteria sank due to the gas vesicles' bursting when the pressure was greater than 0.4 MPa. Gas vesicles and structure after pressure were reformed with the lapse of time, under 1 000 lx, 25 degrees C, after 8 h, 24 h, 48 h, the reformed gas vesicles accounted for 31.02%, 45.68%, 81.05% of total gas vesicles before pressuring. Image analysis method is more accurate in the determination for cyanobacteria gas vesicles' volume, while the volume is smaller measured by traditional capillary pressure method.