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Humans, Communication, Science, Research, Cultural Diversity, Societies, Scientific, Puerto Rico, Social Networking, Workforce, Developmental Biology, Biological Sciences, Agricultural and Veterinary Sciences, and Medical and Health Sciences

Cell Line, Animals, Humans, Mice, Retinoblastoma, Aneuploidy, Chromosomal Instability, Intracellular Signaling Peptides and Proteins, Retinoblastoma Protein, Protein Kinase Inhibitors, Xenograft Model Antitumor Assays, Sequence Analysis, DNA, Genomics, Cell Death, Cell Survival, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Mutation, Genes, Retinoblastoma, Protein-Tyrosine Kinases, Molecular Targeted Therapy, Syk Kinase, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Genes, Sequence Analysis, DNA, and General Science & Technology

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

Multidisciplinary, Multidisciplinaire, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Ophtalmologie, Ophthalmology, Tumeurs et pseudotumeurs de l'oeil, orbite, paupière, appareil lacrymal, Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus, Cancer, Cáncer, Génétique, Genetics, Genética, Homme, Human, Hombre, Pathologie de l'oeil, Eye disease, Ojo patología, Pathologie du système nerveux, Nervous system diseases, Sistema nervioso patología, Rétinopathie, Retinopathy, Retinopatía, Tumeur maligne, Malignant tumor, Tumor maligno, Enfant, Child, Niño, Epigénétique, Epigenetics, Epigenética, Gène onc cellulaire, C-Onc gene, Gen onc celular, Gène rétinoblastome, Retinoblastoma gene, Gen retinoblastoma, Gène suppresseur tumeur, Tumor suppressor gene, Gen supresor tumor, Génome, Genome, Genoma, Mutation, Mutación, Protooncogène, Protooncogene, Protooncogen, Rétinoblastome, Retinoblastoma, Thérapeutique ciblée, Targeted therapy, Terapéutica dirigida, Traitement, Treatment, Tratamiento, Instabilité génétique, Genetic instability, Inestabilidad genética, and Tyrosine protein kinase Syk

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

Medical oncology, Cancérologie, Pharmacology drugs, Pharmacologie, galénique, Sciences biologiques et medicales, Biological and medical sciences, Sciences medicales, Medical sciences, Pharmacologie. Traitements medicamenteux, Pharmacology. Drug treatments, Anticancéreux, Antineoplastic agents, Tumeurs, Tumors, Ophtalmologie, Ophthalmology, Tumeurs et pseudotumeurs de l'oeil, orbite, paupière, appareil lacrymal, Tumors and pseudotumors of the eye, orbit, eyelid, lacrimal apparatus, Rétinopathies, Retinopathies, Cancer, Cáncer, Homme, Human, Hombre, Pathologie de l'oeil, Eye disease, Ojo patología, Pathologie du système nerveux, Nervous system diseases, Sistema nervioso patología, Rétinopathie, Retinopathy, Retinopatía, Tumeur maligne, Malignant tumor, Tumor maligno, Ciblage, Targeting, Blancado, Cible, Target, Blanco, Enfant, Child, Niño, Gène TP53, TP53 Gene, Gen TP53, Gène suppresseur tumeur, Tumor suppressor gene, Gen supresor tumor, Rétinoblastome, Retinoblastoma, Gène p53, Nutline, and Nutlin

Retinoblastoma is a rare childhood cancer of the retina that begins in utero and is diagnosed in the first years of life. The goals of retinoblastoma treatment are ocular salvage, vision preservation, and reduction of short- and long-term side effects without risking mortality because of tumor dissemination. To identify better chemotherapeutic combinations for the treatment of retinoblastoma, several groups have developed genetic mouse models and orthotopic xenograft models of human retinoblastoma for preclinical testing. Previous studies have implicated the MDMX protein in the suppression of the p53 pathway in retinoblastoma and shown that the MDM2/MDMX antagonist, Nutlin-3a, can efficiently induce p53-mediated cell death in retinoblastoma cell lines. However, Nutlin-3a cannot be administered systemically to treat retinoblastoma, because it has poor penetration across the blood-ocular barrier. Therefore, we developed an ocular formulation of Nutlin-3a, Nutlin-3aOC, and tested the pharmacokinetics and efficacy of this new formulation in genetic and human retinoblastoma orthotopic xenograft models of retinoblastoma. Here, we show that Nutlin-3aoc specifically and efficiently targets the p53 pathway and that the combination of Nutlin-3aoc with systemic topotecan is a significantly better treatment for retinoblastoma than currently used chemotherapy in human orthotopic xenografts. Our studies provide a new standardized approach to evaluate and prioritize novel agents for incorporation into future clinical trials for retinoblastoma.

NEURONS, ELECTROPHYSIOLOGY, SENSORY receptors, HAIR cells, and COCHLEA

Type I and type II spiral ganglion neurons convey auditory information from the sensory receptors in the cochlea to the CNS. The numerous type I neurons have been extensively characterized, but the small population of type II neurons with their unmyelinated axons are undetectable with most recording methods. Despite the paucity of information about the type II neurons, it is clear that they must have a significant role in sound processing because they innervate the large number of outer hair cells that are critical for maintaining normal responses to stimuli. To elucidate the function of type II neurons, we have developed an approach for studying their electrophysiological features in vitro. Type II neurons obtained from postnatal day 6-7 mice displayed distinctly different firing properties than type I neurons. They showed slower accommodation, lower action potential thresholds, and more prolonged responses to depolarizing current injection than the type I neurons. These differences were most evident in neurons from the basal, high-frequency region of the cochlea. The basal type I neurons displayed uniformly fast firing features, whereas the basal type II neurons showed particularly slow accommodation and responses to depolarization. Interestingly, neurons from the apical, low-frequency region of the cochlea showed the opposite trend. These data suggest that the type I and type II neurons have specialized electrophysiological characteristics tailored to their different roles in auditory signal processing. In particular, the type II neuron properties are consistent with cells in other sensory systems that receive convergent synaptic input for high-sensitivity stimulus detection. [ABSTRACT FROM AUTHOR]