Efficacy and Safety of Prostaglandin D2 Receptor 2 Antagonism with Fevipiprant for Patients with Asthma: a Systematic Review and Meta-analysis of Randomized Controlled Trials.

PURPOSE OF REVIEW: Accumulating evidence has shown that prostaglandin D2 (PGD2)-chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) pathway plays an important role in promoting eosinophilic airway inflammation in asthma. We aimed to assess the efficacy and safety of CRTH2 antagonist fevipiprant in patients with persistent asthma compared with placebo. RECENT FINDINGS: We identified eligible studies by searching PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. The study was registered as CRD 42020221714 ( http://www.crd.york.ac.uk/PROSPERO ). Ten randomized controlled trials with 7902 patients met our inclusion criteria. A statistically significant benefit of fevipiprant compared with placebo was shown in improving forced expiratory volume in 1 s (MD 0.05 L, 95% CI: 0.02 to 0.07; p < 0.0001), Asthma Control Questionnaire score (MD -0.10, 95% CI: -0.16 to -0.04; p = 0.001), and Asthma Quality of Life Questionnaire score (MD 0.08, 95% CI: 0.03 to 0.13; p = 0.003). Fevipiprant decreased number of patients with at least one asthma exacerbation requiring administration of systemic corticosteroids for 3 days or more (RR 0.86, 95% CI: 0.77 to 0.97; p = 0.01). Some benefits were a little more pronounced in the high eosinophil population (with an elevated blood eosinophil count or sputum eosinophil percentage) and in the 450 mg dose group. Fevipiprant was well tolerated with no safety issues compared with placebo. Fevipiprant could safely improve asthma outcomes compared to placebo. However, most of the differences didn't reach the minimal clinically important difference (MCID), thus the clinical benefits remained to be confirmed.

The Role of Group 3 Innate Lymphoid Cells in Lung Infection and Immunity.

The lung is constantly exposed to environmental particulates such as aeroallergens, pollutants, or microorganisms and is protected by a poised immune response. Innate lymphoid cells (ILCs) are a population of immune cells found in a variety of tissue sites, particularly barrier surfaces such as the lung and the intestine. ILCs play a crucial role in the innate immune system, and they are involved in the maintenance of mucosal homeostasis, inflammation regulation, tissue remodeling, and pathogen clearance. In recent years, group 3 innate lymphoid cells (ILC3s) have emerged as key mediators of mucosal protection and repair during infection, mainly through IL-17 and IL-22 production. Although research on ILC3s has become focused on the intestinal immunity, the biology and function of pulmonary ILC3s in the pathogenesis of respiratory infections and in the development of chronic pulmonary inflammatory diseases remain elusive. In this review, we will mainly discuss how pulmonary ILC3s act on protection against pathogen challenge and pulmonary inflammation, as well as the underlying mechanisms.

[Osteopontin expression and its relation to invasion and metastases in gastric cancer].

OBJECTIVE: To investigate the correlation between expression of the osteopontin (OPN) and invasion and metastases in gastric cancer. METHODS: The expression of OPN, NF-kappaB p65 and matrix metallo-proteinase 9 (MMP-9) was detected by immunohistochemistry in non-cancer gastric tissue (n = 12 cases) and gastric cancer tissue (n = 72 cases). RESULTS: (1) OPN, NF-kappaB p65 and MMP-9 were not expressed in 12 non-cancer gastric tissue samples(group A). Their expression rates were 43.3%, 40.0% and 46.7% respectively in 30 gastric cancer samples without lymph nodes metastasis (group B), but they increased to 76.9%, 73.1% and 80.8% in 26 gastric cancer samples with lymph nodes metastases (group C), and 87.5%, 81.3% and 93.8% respectively in 16 gastric cancer samples with lymph node and distant metastases (group D). (2) There were statistically significant differences in their expressions between group D and group B (P(a) = 0.004, P(c) = 0.007, P(e) = 0.002), and between group C and group B (P(b) = 0.011, P(d) = 0.013, P(f) = 0.009). (3) Despite some differences in positive expression rates, correlations existed between OPN and NF-kappaB p65, and between NF-kappaB p65 and MMP-9 (P(1) = 0.042, P(2) = 0.013; r(1)= 0.67, r(2)= 0.72). CONCLUSION: Osteopondin espression is closely related to the invasion and metastases of gastric cancer. It may upregulate the expression of metastasis-related molecule MMP-9 by activating NF-kappaB pathway.

[Screening and identification of phage-displayed polypeptides specifically binding to human gastric cancer with high metastatic potential to peritoneum].

OBJECTIVE: By means of phage-display technique, to screen polypeptides that specifically bind to human gastric cancer with high metastatic potential to peritoneum. METHODS: Two human gastric cancer cell lines were used: GC9811-P with high metastatic potential to peritoneum and its wild type parental GC9811, to carry out subtractive screening with a phage display-12 peptide library. RESULTS: After three rounds of screening, 40 phage clones bond to GC9811-P cells were randomly selected. When injected into the peritoneal cavity of nude mice, 6 of the 40 clones did not bind to mouse peritoneum as examined by immunohistochemical staining. They were considered to be capable of binding specifically to GC9811-P cells. Sequence analysis revealed two different exogenous peptides: TLNINRLILPRT and SMSI(X)SPYI(XXX). CONCLUSION: Two peptides have been obtained that specifically bind to a gastric cancer cell variant GC9811-P, which easily disseminates to the peritoneum. Whether or not they could block GC9811-P metastasis to peritoneum in vivo remains to be determined.

Establishment and characterization of a high metastatic potential in the peritoneum for human gastric cancer by orthotopic tumor cell implantation.

The aim of this study was to establish an orthotopic implantation model with high metastasis of gastric cancer to the peritoneum which is more faithful to clinical metastasis. A human gastric carcinoma cell line, GC9811, was injected as a single-cell suspension into the stomach of nude mice. The cells from some peritoneum metastatic foci were expanded in vitro and subsequently implanted to the stomach wall of nude mice. By repeating the in vivo stepwise selection method for four rounds and cloning culture, we obtained a cell line designated GC9811-P, which developed peritoneal metastasis in 13 of 13 (100%) of mice, compared with only 20% of those implanted with parental GC9811. The metastatic foci in the peritoneum showed essentially the same histological appearance as those induced by parental cells. Tumor cell growth of GC9811-P in vitro was faster than that of GC9811. Motility assays demonstrated higher motility of GC9811-P than of GC9811. The adhesive ability of GC9811-P cells to laminin was lower than that of GC9811 cells, whereas the ability of GC9811-P cells to adhere to fibronectin was significantly higher than that of parental cells. Differences between GC9811-P and their parental GC9811 cells were found in expression levels of various molecules by flow cytometric and western blot. The findings indicated that up-regulation in the expressions of CD155, VEGF, syndecan-1, and syndecan-2 or down-regulation in the expressions of IL-6 and E-cadherin play an important role in the peritoneal metastasis of human gastric carcinoma cells. The high-metastatic cell line appears to be useful for investigating the mechanisms of peritoneal metastasis and preventing peritoneal metastasis of human gastric cancer.

Phage display selection of peptides that inhibit metastasis ability of gastric cancer cells with high liver-metastatic potential.

Organ-specific metastasis is an important character of cancer cells. Cancer cells that can metastasize to a special organ were thought to have different proteins in cell membrane, which might have potential utility as diagnostic markers and therapeutic targets. In the present work, based on high liver-metastatic gastric cancer cells, XGC9811-L, a screening approach with phage displayed peptide library, was successfully used to isolate 8-mer peptide ligands binding to the target cells. The phage20 had the highest binding efficiency to XGC9811-L cells, which also displayed remarkable cell specificity. Peptide20 that was displayed on phage20 could suppress the motility and invasion of XGC9811-L significantly. The adhesive ability of XGC9811-L to collagen IV was also inhibited by peptide20. Furthermore, phage20 could significantly reduce the incidence of liver metastasis of gastric cancer transplanted into nude mice and was also beneficial for the reduction the number of metastatic nodules in the liver. In conclusion, the phage display is an effective method to screen for the new molecules associated with organ-specific metastasis. The selected peptide20 can reverse the liver metastasis behavior of the gastric cancer cells.