ObjectiveTo develop a gastric cancer (GC) risk prediction rule as an initial prescreening tool to identify individuals with a high risk prior to gastroscopy.DesignThis was a nationwide multicentre cross-sectional study. Individuals aged 40–80 years who went to hospitals for a GC screening gastroscopy were recruited. Serum pepsinogen (PG) I, PG II, gastrin-17 (G-17) and anti-Helicobacter pylori IgG antibody concentrations were tested prior to endoscopy. Eligible participants (n=14 929) were randomly assigned into the derivation and validation cohorts, with a ratio of 2:1. Risk factors for GC were identified by univariate and multivariate analyses and an optimal prediction rule was then settled.ResultsThe novel GC risk prediction rule comprised seven variables (age, sex, PG I/II ratio, G-17 level, H. pylori infection, pickled food and fried food), with scores ranging from 0 to 25. The observed prevalence rates of GC in the derivation cohort at low-risk (≤11), medium-risk (12–16) or high-risk (17–25) group were 1.2%, 4.4% and 12.3%, respectively (p<0.001).When gastroscopy was used for individuals with medium risk and high risk, 70.8% of total GC cases and 70.3% of early GC cases were detected. While endoscopy requirements could be reduced by 66.7% according to the low-risk proportion. The prediction rule owns a good discrimination, with an area under curve of 0.76, or calibration (p<0.001).ConclusionsThe developed and validated prediction rule showed good performance on identifying individuals at a higher risk in a Chinese high-risk population. Future studies are needed to validate its efficacy in a larger population.

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor–stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.

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BackgroundGene duplication is the primary force of new gene evolution. Deciphering whether a pair of duplicated genes has evolved divergent functions is often challenging. The zebrafish is uniquely positioned to provide insight into the process of functional gene evolution due to its amenability to genetic and experimental manipulation and because it possess a large number of duplicated genes.Methodology/Principal FindingsWe report the identification and characterization of two hypoxia-inducible genes in zebrafish that are co-ortholgs of human IGF binding protein-1 (IGFBP-1). IGFBP-1 is a secreted protein that binds to IGF and modulates IGF actions in somatic growth, development, and aging. Like their human and mouse counterparts, in adult zebrafish igfbp-1a and igfbp-1b are exclusively expressed in the liver. During embryogenesis, the two genes are expressed in overlapping spatial domains but with distinct temporal patterns. While zebrafish IGFBP-1a mRNA was easily detected throughout embryogenesis, IGFBP-1b mRNA was detectable only in advanced stages. Hypoxia induces igfbp-1a expression in early embryogenesis, but induces the igfbp-1b expression later in embryogenesis. Both IGFBP-1a and -b are capable of IGF binding, but IGFBP-1b has much lower affinities for IGF-I and -II because of greater dissociation rates. Overexpression of IGFBP-1a and -1b in zebrafish embryos caused significant decreases in growth and developmental rates. When tested in cultured zebrafish embryonic cells, IGFBP-1a and -1b both inhibited IGF-1-induced cell proliferation but the activity of IGFBP-1b was significantly weaker.Conclusions/SignificanceThese results indicate subfunction partitioning of the duplicated IGFBP-1 genes at the levels of gene expression, physiological regulation, protein structure, and biological actions. The duplicated IGFBP-1 may provide additional flexibility in fine-tuning IGF signaling activities under hypoxia and other catabolic conditions.