Mind the target: programmed death ligand 1 in oesophagogastric cancers.

Purpose Of Review: Metastatic oesophagogastric cancers carry a prognosis of generally less than 2 years despite current treatment. There has been recent excitement in the field focused on immune checkpoint inhibition though anti-PD-1 antibodies. In this article, we review recent phase 3 clinical trials evaluating first line PD-L1 inhibition in metastatic HER-2-negative oesophagogastric cancers and discuss future questions and challenges in the field.

Cytoarchitectural changes in the olfactory bulb of Parkinson's disease patients.

Olfactory dysfunction is associated with nearly all the cases of Parkinson's disease (PD) and typically manifests years before motor symptoms are detected. The cellular mechanisms underlying this dysfunction, however, are not understood. In this study, olfactory bulbs (OBs) from male control and PD subjects were examined by histology for changes in cytoarchitecture.

Nucleotide sequence conservation of novel and established -regulatory sites within the tyrosine hydroxylase gene promoter.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis and its gene proximal promoter ( < 1 kb upstream from the transcription start site) is essential for regulating transcription in both the developing and adult nervous systems. Several putative regulatory elements within the proximal promoter have been reported, but evolutionary conservation of these elements has not been thoroughly investigated. Since many vertebrate species are used to model development, function and disorders of human catecholaminergic neurons, identifying evolutionarily conserved transcription regulatory mechanisms is a high priority.

Regulation of tyrosine hydroxylase transcription by hnRNP K and DNA secondary structure.

Regulation of tyrosine hydroxylase gene (Th) transcription is critical for specifying and maintaining the dopaminergic neuronal phenotype. Here we define a molecular regulatory mechanism for Th transcription conserved in tetrapod vertebrates. We show that heterogeneous nuclear ribonucleoprotein (hnRNP) K is a transactivator of Th transcription.

Adult subventricular zone neural stem cells as a potential source of dopaminergic replacement neurons.

Clinical trials engrafting human fetal ventral mesencephalic tissue have demonstrated, in principle, that cell replacement therapy provides substantial long-lasting improvement of motor impairments generated by Parkinson's Disease (PD). The use of fetal tissue is not practical for widespread clinical implementation of this therapy, but stem cells are a promising alternative source for obtaining replacement cells. The ideal stem cell source has yet to be established and, in this review, we discuss the potential of neural stem cells in the adult subventricular zone (SVZ) as an autologous source of replacement cells.

Epigenetic control of neurotransmitter expression in olfactory bulb interneurons.

Defining the molecular mechanisms that underlie development and maintenance of neuronal phenotypic diversity in the CNS is a fundamental challenge in developmental neurobiology. The vast majority of olfactory bulb (OB) interneurons are GABAergic and this neurotransmitter phenotype is specified in migrating neuroblasts by transcription of either or both glutamic acid decarboxylase 1 (Gad1) and Gad2. A subset of OB interneurons also co-express dopamine, but transcriptional repression of tyrosine hydroxylase (Th) suppresses the dopaminergic phenotype until these neurons terminally differentiate.

Physiological and anatomical evidence for an inhibitory trigemino-oculomotor pathway in the cat.

During blink down-phase, the levator palpebrae superioris (levator) muscle is inactivated, allowing the orbicularis oculi muscle to act. For trigeminal reflex blinks, the excitatory connections from trigeminal sensory nuclei to the facial nucleus have been described, but the pathway whereby the levator is turned off have not. We examined this question by use of both physiological and anatomical approaches in the cat.

Differential regulation of dopaminergic gene expression by Er81.

A recent study proposed that differentiation of dopaminergic neurons requires a conserved "dopamine motif" (DA-motif) that functions as a binding site for ETS DNA binding domain transcription factors. In the mammalian olfactory bulb (OB), the expression of a set of five genes [including tyrosine hydroxylase (Th)] that are necessary for differentiation of dopaminergic neurons was suggested to be regulated by the ETS-domain transcription factor ER81 via the DA-motif. To investigate this putative regulatory role of ER81, expression levels of these five genes were compared in both olfactory bulbs of adult wild-type mice subjected to unilateral naris closure and the olfactory bulbs of neonatal Er81 wild-type and mutant mice.

Histone deacetylase inhibitors de-repress tyrosine hydroxylase expression in the olfactory bulb and rostral migratory stream.

Most olfactory bulb (OB) interneurons are derived from neural stem cells in the subventricular zone (SVZ) and migrate to the OB via the rostral migratory stream (RMS). Mature dopaminergic interneurons in the OB glomerular layer are readily identified by their synaptic activity-dependent expression of tyrosine hydroxylase (TH). Paradoxically, TH is not expressed in neural progenitors migrating in the RMS, even though ambient GABA and glutamate depolarize these progenitors.

Dopamine systems in the forebrain.

The brain contains a number of distinct regions that share expression ofdopamine (DA) and its requisite biosynthetic machinery, but otherwise encompass a diverse array of features and functions. Across the vertebrate family, the olfactory bulb (OB) contains the major DA system in the forebrain. OB DA cells are primarily periglomerular interneurons that define the glomerular structures in which they receive innervation from olfactory receptor neurons as well as mitral and tufted cells, the primary OB output neurons.

Chemoreception scientists gather under the Florida sun: The 31st Annual Association for Chemoreception Sciences meeting.

The 31st Annual Association for Chemoreception Sciences (AChemS) met in Sarasota, Florida April 22-26, 2009, attracting approximately 600 registrants and nearly 400 abstracts. In addition to poster and platform presentations, the program offered symposia, special lectures, and various National Institutes of Health (NIH)-sponsored workshops, including one on computational approaches to olfaction.

Expression of EGR-1 in a subset of olfactory bulb dopaminergic cells.

In the adrenal medulla, binding of the immediate early gene (IEG) proteins, EGR-1 (ZIF-268/KROX-24/NGFI-A) and AP-1, to the tyrosine hydroxylase (Th) proximal promoter mediate inducible Th expression. The current study investigated the potential role of EGR-1 in inducible Th expression in the olfactory bulb (OB) since IEGs bound to the AP-1 site in the Th proximal promoter are also necessary for activity-dependent OB TH expression. Immunohistochemical analysis of a naris-occluded mouse model of odor deprivation revealed weak EGR-1 expression levels in the OB glomerular layer that were activity-dependent.

gamma-Aminobutyric acid-mediated regulation of the activity-dependent olfactory bulb dopaminergic phenotype.

gamma-Aminobutyric acid (GABA) regulates the proliferation and migration of olfactory bulb (OB) interneuron progenitors derived from the subventricular zone (SVZ), but the role of GABA in the differentiation of these progenitors has been largely unexplored. This study examines the role of GABA in the differentiation of OB dopaminergic interneurons using neonatal forebrain organotypic slice cultures prepared from transgenic mice expressing green fluorescent protein (GFP) under the control of the tyrosine hydroxylase (Th) gene promoter (ThGFP). KCl-mediated depolarization of the slices induced ThGFP expression.

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model.

Mitochondrial dysfunction, oxidative stress and reductions in thiamine-dependent enzymes have been implicated in multiple neurological disorders including Alzheimer's disease (AD). Experimental thiamine deficiency (TD) is an established model for reducing the activities of thiamine-dependent enzymes in brain. TD diminishes thiamine-dependent enzymes throughout the brain, but produces a time-dependent selective neuronal loss, glial activation, inflammation, abnormalities in oxidative metabolism and clusters of degenerating neurites in only specific thalamic regions.

Olfactory cell derivation and migration.

This special issue of the Journal of Molecular Histology is devoted to the unique phenomena of migration and adult neurogenesis observed in the olfactory system. Neural progenitors migrate from the olfactory placode and epithelium (OE) into the central nervous system (CNS) and from the forebrain ventricular region to the olfactory bulb (OB). Not unexpectedly, there are a number of controversies with regard to the mechanisms regulating these phenomena in both developing and adult animals.

ER81 and CaMKIV identify anatomically and phenotypically defined subsets of mouse olfactory bulb interneurons.

The mechanisms underlying dopamine (DA) phenotypic differentiation in the olfactory bulb (OB) have not yet been fully elucidated and are the subject of some controversy. OB DA interneurons destined for the glomerular layer were shown to originate in the subventricular zone (SVZ) and in the rostral migratory stream (RMS). The current study investigated whether calcium/calmodulin-dependent protein kinase IV (CaMKIV) either alone or together with the Ets transcription factor ER81 was necessary for phenotypic determination during migration of progenitors.

Temporal and spatial disparity in cFOS expression and dopamine phenotypic differentiation in the neonatal mouse olfactory bulb.

The mammalian olfactory bulb (OB) is among the few regions in adult brain which generates interneurons. A subpopulation of these phenotypically diverse interneurons is dopaminergic (DA) periglomerular cells. Full phenotypic development as indicated by expression of tyrosine hydroxylase (TH), the first enzyme in DA biosynthesis, requires afferent activity or equivalent depolarizing conditions.

A method for a more complete in vitro Parkinson's model: slice culture bioassay for modeling maintenance and repair of the nigrostriatal circuit.

Slice culture model systems provide a unique opportunity to monitor and lesion brain circuits in a dish. Using a novel approach, we have generated parasagittal slices from mouse brains that preserve, throughout the culture process, the nigrostriatal circuit. These slices can be cultured for approximately 4 weeks with maintenance of normal neuronal cytoarchitecture.

Transient expression of tyrosine hydroxylase promoter/reporter gene constructs in the olfactory epithelium of transgenic mice.

Maturation and survival of olfactory receptor neurons (ORNs) are hypothesized to depend on trophic support from the olfactory bulb during both development and regeneration of the olfactory epithelium (OE). The current study characterized transgene expression in two independently derived transgenic mouse lines in which 9 kb of tyrosine hydroxylase (TH) promoter was utilized to drive either enhanced green fluorescent protein (TH/eGFP) or LacZ (TH/beta-gal) reporters. Transgene expression, found primarily on dorsal aspects of the OE, the dorsal septum and endoturbinate II, resembled the Zone one distribution of olfactory receptor genes.

Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons.

Septin 5, a parkin substrate, is a vesicle- and membrane-associated protein that plays a significant role in inhibiting exocytosis. The regulatory function of Septin 5 in dopaminergic (DAergic) neurons of substantia nigra (SN), maintained at relatively low levels, has not yet been delineated. As loss of function mutations of parkin are the principal cause of a familial Parkinson's disease, a prevailing hypothesis is that the loss of parkin activity results in accumulation of Septin 5 which confers neuron-specific toxicity in SN-DAergic neurons.

Differentiation of the dopaminergic phenotype in the olfactory system of neonatal and adult mice.

Olfactory bulb (OB) interneurons are derived primarily postnatally from progenitors in the anterior subventricular zone (SVZa) and migrate to the OB in the rostral migratory stream (RMS). Progenitors differentiate into phenotypically diverse granule and periglomerular cells by as yet undefined mechanisms. To visualize spatiotemporal aspects of periglomerular dopamine (DA) neuron differentiation, two independently derived transgenic mouse lines were analyzed with a 9-kb tyrosine hydroxylase (TH) promoter to drive either a LacZ or an enhanced green fluorescent protein (EGFP) reporter gene.

Cortical and striatal expression of tyrosine hydroxylase mRNA in neonatal and adult mice.

1. Elucidating the mechanisms underlying regulation of the dopamine (DA) phenotype during development and in adult animals was a major focus of many of the students and postdoctoral fellows in the Laboratory of Dr Donald Reis. In one series of studies, expression of tyrosine hydroxylase (TH), the first enzyme in the DA biosynthetic pathway, was induced in primary cultures prepared from the cortical anlage of embryonic day 13 (E13)-E17 rat embryos.

Dlx-1 and Dlx-2 expression in the adult mouse brain: relationship to dopaminergic phenotypic regulation.

Expression of the homeodomain-containing transcription factors Dlx-1 and Dlx-2 in the lateral (LGE) and medial (MGE) ganglionic eminences, subpallial embryonic structures, is required for generation of telencephalic interneurons. LGE- and MGE-derived progenitors migrate and populate a number of forebrain structures, including the cortex, hippocampus, and olfactory bulb (OB). Previous reports focusing on embryogenesis of telencephalic neurons in Dlx-1 and Dlx-2 null mice suggested a specific role for these genes in expression of the OB dopamine (DA) phenotype.

Olfactory signal transduction in the mouse septal organ.

The septal organ, a distinct chemosensory organ observed in the mammalian nose, is essentially a small island of olfactory neuroepithelium located bilaterally at the ventral base of the nasal septum. Virtually nothing is known about its physiological properties and function. To understand the nature of the sensory neurons in this area, we studied the mechanisms underlying olfactory signal transduction in these neurons.