GABA is an inhibitory neurotransmitter in the neural circuit regulating metamorphosis in Ilyanassa obsoleta

The marine mud snail, Ilyanassa obsoleta, displays a biphasic life cycle. The initial phase consists of weakly swimming larval animals with ciliated feeding structures on the head, the velar lobes. The second phase consists of adult animals residing on intertidal mudflats as obligate omnivores. Metamorphosis, the event that links these life history stages, is initiated by external stimuli but coordinated by internal signaling molecules. Internally, molluscan metamorphosis includes neurotransmitters that modify the behavior of cells in neural circuits. For several species of molluscs, including abalone and scallops, larval metamorphosis can be induced by the external application of the neurotransmitter, gamma-aminobutyric acid (GABA). In this situation, GABA is presumed to mimic the actions of food-related ligands that bind to external sensory receptors. GABA is the only neurotransmitter known to act in such a fashion. In contrast, results of our preliminary experiments with I. obsoleta strongly support the hypothesis that GABA works internally in this species as a neurotransmitter in the larval central nervous system (CNS) to inhibit metamorphosis. External application of GABA to metamorphically competent larvae of I. obsoleta does not elicit metamorphosis, but does repress metamorphic induction. I utilized a battery of GABAergic reagents to modify internal GABAergic activity to address the hypothesis that GABA inhibits metamorphosis due to its actions within the larval CNS. My results strongly suggest that GABA inhibits metamorphosis in this molluscan model organism. My results indicate that GABA acts downstream from or directly on serotonergic neurons to decrease the metamorphosis-inducing effects of serotonin

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Next generation sequencing: profiling gallbladder cancer

This journal suppl. entitled: 2015 Gastrointestinal Symposium AbstractsGeneral Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract: abstract no. 286BACKGROUND: Molecular profiling data of GBC is scant and it is often included with other biliary cancers for analysis, which may hinder advancing drug discovery. METHODS: Archival formalin fixed paraffin embedded (FFPE) tissue of GBC from 2 research hospitals in Toronto (n=21) and Hong Kong (n=21) were analyzed by MassARRAY Sequenom panel (23 genes, 279 mutations), or by next general sequencing (NGS) using Proton or Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥500x coverage). Results of other biliary cancer and ampullary cancer from an ongoing profiling project were also reported. RESULTS: Twelve biliary cancer samples first analyzed with Sequenom revealed no mutations. Reanalysis with NGS of these yielded mutations in 5. All subsequent samples were analyzed with NGS (n=57). Mutations were identified in 80% [53 mutations in 42 GBC, 8 mutations in 9 intrahepatic cholangiocarcinoma (IHC), 7 mutations in 6 hilar/distal bile duct cancers (DBD)]. The most frequent mutations in GBC were TP53 and SMAD4, and KRAS mutation was found in 7% (Table). PIK3CA mutation was found in 5% of GBC but not the other biliary cancers, and IDH1 mutation was exclusive for IHC, in agreement with published literature. TP53 mutations in GBC patients did not correlate with gender, tumor grade, survival, or treatment response to gemcitabine-based chemotherapy. There was no difference in mutation patterns in GBC between 2 institutions/countries. CONCLUSIONS: NGS can be utilized for molecular profiling of biliary cancer, detecting potentially actionable targets in the majority of cases. Our preliminary data suggests GBC may have its own molecular profile, deserving special consideration in trial design for biliary cancer. To our knowledge the current study is the biggest cohort of NGS analysis for GBC