Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response.

Mammalian polo-like kinase (Plk) acts at various stages in early and late mitosis. Plk is phosphorylated and activated in mitosis, and the proper subcellular localization of Plk is essential for mitotic regulation. We have observed that overexpression of the C-terminal domain of Plk is more effective than wild-type or kinase-defective Plk in causing mitotic delay or arrest. The specific activity of Plk with C-terminal deletions or substitution of aspartate for threonine-210 is increased severalfold relative to wild type. We show in this communication that the C-terminal domain can bind to fulllength or the catalytic domain of Plk and inhibit its kinase activity, and that this binding is disrupted when threonine-210 is substituted with an aspartic acid residue. The C-terminal domain binds unphosphorylated Plk from G2 arrested cells, but not phosphorylated Plk from mitotic cells. Green fluorescent protein-C-terminal Plk is localized at the centrosome and the midbody of transfected cells as shown previously for full-length enzyme. These and other data indicate that although the C terminus serves to regulate Plk kinase activity, the localization of the C terminus at the centrosome and other sites in transfected cells may block the correct localization of endogenous Plk. intramolecular binding ͉ inhibition ͉ mitosis ͉ mammalian cells

We evaluated immunometabolic functions of novel Lactobacillus fermentum strains (KBL374 and KBL375) isolated from feces of healthy Koreans. The levels of inflammatory cytokines, such as interleukin (IL)-2, interferon-γ, IL-4, IL-13, and IL-17A, were decreased, and that of the antiinflammatory cytokine IL-10 was increased, in human peripheral blood mononuclear cells (PBMCs) treated with the L. fermentum KBL374 or KBL375 strain. When these strains were orally administered to mice with dextran sulfate sodium (DSS)-induced colitis, both L. fermentum KBL374 and KBL375 showed beneficial effects on body weight, disease activity index score, colon length, cecal weight, and histological scores. Furthermore, both L. fermentum KBL374 and KBL375 modulated the innate immune response by improving gut barrier function and reducing leukocyte infiltration. Consistent with the PBMC data, both L. fermentum KBL374-and KBL375-treated DSS mice demonstrated decreased Th1-, Th2-, and Th17-related cytokine levels and increased IL-10 in the colon compared with the DSS control mice. Administration of L. fermentum KBL374 or KBL375 to mice increased the CD4+CD25+Foxp3+Treg cell population in mesenteric lymph nodes. Additionally, L. fermentum KBL374 or KBL375 administration reshaped and increased the diversity of the gut microbiota. In particular, L. fermentum KBL375 increased the abundance of beneficial microorganisms, such as Lactobacillus spp. and Akkermansia spp. Both L. fermentum KBL374 and KBL375 may alleviate inflammatory diseases, such as inflammatory bowel disease, in the gut by regulating immune responses and altering the composition of gut microbiota.

PURPOSE Adjuvant chemotherapy after D2 gastrectomy is standard for resectable locally advanced gastric cancer (LAGC) in Asia. Based on positive findings for perioperative chemotherapy in European phase III studies, the phase III PRODIGY study (ClinicalTrials.gov identifier: NCT01515748 ) investigated whether neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 could improve outcomes versus standard treatment in Korean patients with resectable LAGC. PATIENTS AND METHODS Patients 20-75 years of age, with Eastern Cooperative Oncology Group performance status 0-1, and with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N+ or T4Nany) were randomly assigned to D2 surgery followed by adjuvant S-1 (40-60 mg orally twice a day, days 1-28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1-14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary objective was progression-free survival (PFS) with CSC versus SC. Two sensitivity analyses were performed: intent-to-treat and landmark PFS analysis. RESULTS Between January 18, 2012, and January 2, 2017, 266 patients were randomly assigned to CSC and 264 to SC at 18 Korean study sites; 238 and 246 patients, respectively, were treated (full analysis set). Follow-up was ongoing in 176 patients at data cutoff (January 21, 2019; median follow-up 38.6 months [interquartile range, 23.5-62.1]). CSC improved PFS versus SC (adjusted hazard ratio, 0.70; 95% CI, 0.52 to 0.95; stratified log-rank P = .023). Sensitivity analyses confirmed these findings. Treatments were well tolerated. Two grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant treatment. CONCLUSION PRODIGY showed that neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, is effective and tolerable in Korean patients with LAGC.

Cell division is characterized by orchestrated events of chromosome segregation, distribution of cellular organelles, and the eventual partitioning and separation of the two daughter cells. Mitotic kinases, including polo-like kinases (Plk), influence multiple events in mitosis. In yeast two-hybrid screens using mammalian Plk C-terminal domain baits, we have identified Golgi peripheral protein GRASP65 (Golgi reassembly stacking protein of 65 kDa) as a Plk-binding protein. GRASP65 appears to function in the postmitotic reassembly of Golgi stacks. In this report we demonstrate binding between Plk and GRASP65 and provide in vitro and in vivo evidence that Plk is a GRASP65 kinase. Moreover, we show that Cdc2 can also phosphorylate GRASP65. In addition, we present data which support the observation that the conserved C terminus of Plk is important for its function. Deletion or frameshift mutations in the conserved C-terminal domain of Plk greatly diminish its ability to phosphorylate GRASP65. These and previous findings suggest that phosphorylation of Golgi components by mitotic kinases may regulate mechanisms of Golgi inheritance during cell division.