Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, and response to therapy. However, a number of small molecule inhibitors under development vary in strength of subset and pathway-specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes. We investigated the effects of Notch pathway inhibition in glioma tumor initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing of 16 GICs showed differential growth responses to the inhibitors, stratifying GICs into responders and non-responders. Responder GICs had an enriched proneural gene signature in comparison to non-responders. Also gene set enrichment analysis revealed 17 genes set representing active Notch signaling components NOTCH1, NOTCH3, HES1, MAML1, DLL-3, JAG2 etc., enriched in responder group. Analysis of TCGA expression data set identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation suggesting γ-secretase inhibitors might be of potential value to treat that particular group of proneural GBM. Inhibition of Notch pathway by γ-secretase inhibitor treatment attenuated proliferation and self-renewal of responder GICs and induces both neuronal and astrocytic differentiation. In vivo evaluation demonstrated prolongation of median survival in an intracranial mouse model. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ-secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy.
Glioma stem cells (GSCs) have the capacity to repopulate tumors and mediate resistance to radiotherapy and chemotherapy. The Notch signaling pathway is important in proliferation, stem cell maintenance, cell differentiation, and tumorigenesis in GSCs. In this study, we compared CD133, Notch, and VEGF expressions in histological sections of primary and recurrent glioblastomas after radiotherapy and chemotherapy. In vitro study, the γ-secretase inhibitor inhibited NICD, Hes1 and pVEGFR2 expressions in GSCs. GSCs cultured under endothelial conditions undergo endothelial differentiation. Tumor samples were collected from 27 patients at the time of tumor recurrence. We used immunohistochemical techniques to compare expression of CD133, Notch-1 and VEGF. Expressions of CD133-, Notch-1-, and VEGF-positive glioma cells were higher in recurrent glioblastoma after radiotherapy and chemotherapy. To determine the clinical importance of Notch-1 expression in glioblastoma, we analyzed 15 patients who had received bevacizumab therapy followed by a second surgery at recurrence. OS was significantly longer in cases with Notch-1 negativity (8.8 months) than in those with I Notch-1 positivity (6.8 months). We noted that GSCs have the potential for endothelial differentiation with Notch activity. We believe that Notch-1 is a potential target and/or biomarker for antiangiogenic treatments.
Black lesions on shoots of European pear trees observed in an orchard in Yamagata Prefecture in May 2007 were suspected to be caused by a bacterial pathogen. The surface of the colonies isolated on a high sucrose medium did not have the crater morphology that is characteristic of E. amylovora bvs. 1-3, and a specific DNA fragment was amplified from the isolates in the PCR using the EprpoD primer set. The partial sequences of the 16S rRNA gene placed the isolates in the genus Erwinia. The isolates differed serologically from E. amylovora biovars and E. pyrifoliae in an Ouchterlony double-diffusion test although their bacterial properties suggested that they are closely related to E. amylovora biovars and E. pyrifoliae. In a DNA-DNA hybridization test, the relatedness between the isolates and E. amylovora biovars or E. pyrifoliae did not exceed 70% level, indicating that they are independent species. Thus, the isolates belongs to the genus Erwnia but are not E. amylovra or E. pyrifoliae. After succulent pear shoots were injected with bacterial suspensions (10 9 , 10 8 , 10 7 and 10 6 cfu/ml) of the isolates, lesions formed with 10 9 and 10 8 cfu/ml, but the disease incidence with 10 8 cfu/ml was much lower than with E. amylovora and E. pyrifoliae. Virulence of the present isolates is thus thought to be very weak. On the basis of these results, we consider that this is a new shoot disease of European pear. In the 2007 season, all affected trees were pulled out after harvest. No symptoms have been observed in field surveys since the fruitlet season in 2007.
Erwinia uzenensis sp. nov., a novel pathogen that affects European pear trees (Pyrus communis L.) Rhim et al., 1999) in that necrotic symptoms on blossoms and fruitlets were not observed in this case. In addition, the symptoms were different from necrotic pear blossoms caused by Erwinia piriflorinigrans (Roselló et al., 2006;Ló pez et al., 2011) in that the necrotic symptoms were limited to blossoms. We isolated 18 pathogenic bacteria (YPPS 950-YPPS 967) from lesions of black shoot disease, and previously completed a preliminary characterization of them (Mizuno et al., 2010). The purpose of the present study was to define their taxonomic status more precisely.All bacteria used in this study were stored at 240 u C in dispersion medium [10 % (w/v) skimmed milk, 1 % (w/v) monosodium glutamate]. Prior to each analysis, the bacteria were streaked on King's medium B (King et al., 1954) or PSA (Wakimoto, 1955 and grown for 48 h at 26 u C. The GenBank/EMBL/DDBJ accession numbers for the 16S rRNA gene, gyrB and rpoD sequences of the reference strains used and the pathogenic strains we isolated are listed in Table S1, available in IJSEM Online.The phenotypic features were determined using the method described by Dye (1968). All tests were performed at 26 u C except for determination of growth at differentThe GenBank/EMBL/DDBJ accession numbers for the 16S rRNA gene, gyrB and rpoD gene sequences of strain YPPS951 T are AB546198, AB546201 and AB546219, respectively. The GenBank/ EMBL/DDBJ accession numbers for the 16S rRNA gene, gyrB and rpoD gene sequences of other strains, YPPS950 and YPPS952 to YPPS967 are available in Table S1.A supplementary figure and two supplementary tables are available with the online version of this paper.
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