Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of prostaglandin D2 and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (−/−) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2−/− mice, blunting CLP-induced lethality in CRTH2−/− mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH2−/− mice, which was associated with higher CXCR2 level in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in WT neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2−/− mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis.
2
Micro abstractIntra-tumor heterogeneity of epidermal growth factor receptor (EGFR) mutations in patients with mixed-type lung adenocarcinoma was analyzed according to histological patterns. Intra-tumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors, and there was a significant correlation between heterogeneity of EGFR mutations and smoking history (P<0.043).
Clinical Practice Points• EGFR mutations are factors predictive of response to EGFR-TKI treatment. However, lung cancer is thought to be the result of the accumulation of genetic alterations over a long course of exposure to a carcinogen, and the existence of intra-tumor heterogeneity of EGFR mutations remains unclear. Thus, the existence of intra-tumor heterogeneity was analyzed in patients with mixed-type lung adenocarcinoma according to histological patterns.• Intra-tumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors, and a significant correlation between heterogeneity of EGFR 3 mutations and smoking history was found.• Response to EGFR-TKIs might be partial and insufficient in tumors having intra-tumor heterogeneity of EGFR mutations. New treatment strategies for patients with lung adenocarcinoma harboring heterogeneous EGFR mutations are needed.
Micro abstractWe compared three PCR methods (mutant-enriched PCR, PNA-LNA PCR and PCR clamp) to detect EGFR mutations in 50 patients with advanced NSCLC. Seventeen were harboring EGFR mutations, five of whom showed discrepancies between the results of different PCR methods. All five responded to gefitinib, which we consider to suggest that the discrepancies were false negatives.
Clinical Practice Points• Several methods have been used to detect EGFR mutations in non-small-cell lung cancer (NSCLC): however, it is not clear which is the most suitable for use in the clinic.• We compared three PCR methods (mutant-enriched PCR, PNA-LNA PCR and PCR clamp) in 50 patients with advanced NSCLC. Seventeen of the patients were harboring EGFR mutations, five of whom showed discrepancies between the results of different PCR methods. All five patients responded to gefitinib.• We considered that all of the discrepancies might be false negatives because the patients responded to gefitinib. To clarify the reasons for the false negatives of each PCR method, and establish the clinical sensitivity and specificity of each method, a large prospective clinical trial is warranted.
AbstractBackground: Epidermal growth factor receptor (EGFR) mutations are predictive of
The histone deacetylase inhibitor trichostatin A protects mice against postinfluenza pneumonia possibly through multiple factors, including decreasing local cell recruitment into the lungs and suppressing systemic inflammation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.