Tumor-associated macrophages play an important role in tumor progression, but whether they exert a tumor-progressive effect remains controversial. Here, we demonstrated that activated macrophage-conditioned medium (AMCM) obtained from RAW macrophages (RAW/AMCM) induced epithelial-mesenchymal transition (EMT) and stimulated the migratory and invasive activities of HepG2 cells, whereas control conditioned media had no effect. Epithelial-cadherin (E-cadherin) and b-catenin staining patterns were altered at the adherens junctions by RAW/AMCM treatment, with an approximately 50% decrease in E-cadherin and b-catenin in the cell membrane. Importantly, levels of b-cateninassociated E-cadherin were also decreased. Following RAW/ AMCM treatment, enhanced activation of c-Src was seen prior to increased tyrosine phosphorylation of b-catenin, and this led to the destabilization of adherens junctions. Pretreatment of HepG2 cells with the Src kinase inhibitor, PP2, completely abolished the effects of RAW/AMCM on the EMT, migration, invasion, and expression and association of E-cadherin and bcatenin. AMCMs obtained from human THP-1 monocytes and mouse peritoneal macrophages also caused disassembly of the adherens junctions and migration of HepG2 cells. Furthermore, inhibition of the epidermal growth factor receptor (EGFR) with gefitinib partially prevented the downregulation of E-cadherin and b-catenin at the adherens junctions and migration behavior induced by RAW/AMCM. Our results suggest that activated macrophages have a tumor-progressive effect on HepG2 cells which involves the c-Src-and EGFR-dependent signaling cascades.

Breathomics is a special branch of metabolomics that quantifies volatile organic compounds (VOCs) from collected exhaled breath samples. Understanding how breath molecules are related to diseases, mechanisms and pathways identified from experimental analytical measurements is challenging due to the lack of an organized resource describing breath molecules, related references and biomedical information embedded in the literature. To provide breath VOCs, related references and biomedical information, we aim to organize a database composed of manually curated information and automatically extracted biomedical information. First, VOCs-related disease information was manually organized from 207 literature linked to 99 VOCs and known Medical Subject Headings (MeSH) terms. Then an automated text mining algorithm was used to extract biomedical information from this literature. In the end, the manually curated information and auto-extracted biomedical information was combined to form a breath molecule database—the Human Breathomics Database (HBDB). We first manually curated and organized disease information including MeSH term from 207 literatures associated with 99 VOCs. Then, an automatic pipeline of text mining approach was used to collect 2766 literatures and extract biomedical information from breath researches. We combined curated information with automatically extracted biomedical information to assemble a breath molecule database, the HBDB. The HBDB is a database that includes references, VOCs and diseases associated with human breathomics. Most of these VOCs were detected in human breath samples or exhaled breath condensate samples. So far, the database contains a total of 913 VOCs in relation to human exhaled breath researches reported in 2766 publications. The HBDB is the most comprehensive HBDB of VOCs in human exhaled breath to date. It is a useful and organized resource for researchers and clinicians to identify and further investigate potential biomarkers from the breath of patients. Database URL: https://hbdb.cmdm.tw

The prognostic implication of BRAF mutant colorectal cancer remains paradoxical. Records of BRAF mutant and wild-type colorectal cancer patients at all stages were reviewed. Clinicopathologic features, including microsatellite instability, CpG islands methylator phenotype, and overall survival, of these patients were analyzed. Between 2005 and 2013, 428 colorectal cancer patients were enrolled in this study. The overall survival between BRAF mutant and wild-type patients with early-stage (stages I and II) colorectal cancer differed nonsignificantly (P = 0.99). By contrast, in late-stage (stages III and IV) patients, the median overall survival of BRAF mutant patients (N = 25) was significantly poorer than that of BRAF wild-type (N = 207) patients (BRAF mutant: 21.3 months (95% confidence interval [CI] 7.1-35.5); BRAF wild-type: 53.5 months (95% CI 37.5-69.5), P < 0.0001). In early-stage patients, we found that BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P < 0.001), and microsatellite instability-high status (P = 0.0013). Conversely, in late-stage patients, BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P = 0.0015) and the right-side colon (P = 0.014). BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer.

BackgroundAnti-programmed death-1 therapy has poor efficacy in mismatch repair-proficient (pMMR) colorectal cancers; however, its efficacy in pMMR gastric cancers remains undetermined. Here, we report the case of a patient with pMMR and microsatellite-stable gastric cancer who exhibited a partial response to salvage anti-programmed death-1 therapy with pembrolizumab.Case presentationInitially, the patient underwent subtotal gastrectomy 4 years ago for early-stage gastric cancer (pT1bN2M0, stage IIA). Immunohistochemical analysis of the tumor revealed strongly positive for HER2/neu. He had received trastuzumab plus pertuzumab, cisplatin, and capecitabine for recurrent tumors since September 2014 for 15 cycles. Disease progression of gastric cancer was found in August 2015. Since September 2015, the patient has received pembrolizumab monotherapy (200 mg as a fixed dose, every 3 weeks) for 3 months and the repeat computed tomography demonstrated a confirmed partial response. The plasma carcinoembryonic antigen also decreased dramatically. Both immunohistochemistry and a polymerase chain reaction-based method revealed that the patient had pMMR gastric cancer.ConclusionsThis case report provides the first report that mismatch repair-proficient and microsatellite-stable gastric cancers can respond well to anti-PD-1 monotherapy and indicates both markers may not sufficiently be predictive of anti-PD-1 therapy resistance in gastric cancer.