Generation of multicellular tumor spheroids with micro-well array for anticancer drug combination screening based on a valuable biomarker of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. More than 30% of patients with diagnosed HCC have abnormally high expression of fibroblast growth factor receptor 4 (FGFR4). Currently, clinical trials for a variety of FGFR4-specific inhibitors have started. However, the effect of these inhibitors is not ideal, and it is necessary to find a drug combination to synergistically exert anti-tumor effects. We found strong correlations between FGFR4 and HCC clinicopathological characteristics in the present study. After grouping patients according to FGFR4 expression, the key gene signatures were inputted the drug-gene related databases, which predicted several potential drug candidates. More importantly, to achieve the reliable and high throughput drug cytotoxicity assessment, we developed an efficient and reproducible agarose hydrogel microwells to generate uniform-sized multicellular tumor spheroids, which provide better mimicry of conventional solid tumors that can precisely represent anticancer drug candidates' effects. Using high content screening, we quickly evaluated the enhanced anti-tumor effects of these combinations. Finally, we demonstrated that Parthenolide is a potential drug that can significantly enhance the clinical efficacy of FGFR4 receptor inhibitors. In general, we offered a new therapeutic way for FGFR4 positive HCC patients.

Biogenic Silica and Organic Carbon Records in Zhoushan Coastal Sea over the Past One Hundred Years and Their Environmental Indications.

The influence of terrestrial and marine input has dramatically changed eutrophication in coastal seas over the past 100 years. In this study, Zhoushan coastal sea (ZCS) is taken as a study area. We studied ZCS as it is a sink of the temporal and spatial variation of primary productivity, dominant species of algae, and the variation of provenance in this area over the past 100 years. We performed analysis using three sediment cores and the carbon and silicon deposition records. The analysis results demonstrate that: (1) The primary productivity in the northern area of the ZCS close to the Yangtze Estuary was the highest comparatively, but it declined slightly before 2010. The primary productivity in the southern area had an increasing trend over the past 100 years. The value of total organic carbon (TOC) in the northern area was relatively high, with an average value of 0.532% over the past 100 years, with a decreasing trend in recent years. On the contrary, TOC in the southern area was relatively low, but it was increased dramatically after 1995. (2) Diatom might play an important role in the variations. The biogenic silica (BSi) and TOC in the northern area showed a synchronous declining trend, while the BSi/TOC ratio did not change significantly. This indicates the algae population structure in this area was relatively stable over the past 100 years. The BSi/TOC ratio decreased continuously in the southern area, indicating that the dominance of diatoms was decreasing continuously. (3) The variation of diatom dominance in this area might have a great relationship with the change of nutrients' provenance. A mean value of stable carbon isotope (δ13C) in the north of Zhoushan was -23.46‱, indicating that the terrestrial-source input was the highest. (4) The change of provenance in the study area was quite different. This illustrates that the terrestrial input impacted the largest area of ZCS while marine input became dominant in the offshore area.