scholarly journals Testing algorithm for identification of patients with TRK fusion cancer

2019 ◽  
Vol 72 (7) ◽  
pp. 460-467 ◽  
Author(s):  
Frédérique Penault-Llorca ◽  
Erin R Rudzinski ◽  
Antonia R Sepulveda
Keyword(s):  
Kinase Inhibitors ◽  
System Development ◽  
In Situ Hybridisation ◽  
Nervous System Development ◽  
Diagnostic Process ◽  
Fluorescence In Situ Hybridisation ◽  
Gene Fusions ◽  
Paediatric Tumours ◽  
Testing Algorithm ◽  
And Function

The neurotrophic tyrosine receptor kinase (NTRK) gene family encodes three tropomyosin receptor kinases (TRKA, TRKB, TRKC) that contribute to central and peripheral nervous system development and function. NTRK gene fusions are oncogenic drivers of various adult and paediatric tumours. Several methods have been used to detect NTRK gene fusions including immunohistochemistry, fluorescence in situ hybridisation, reverse transcriptase polymerase chain reaction, and DNA- or RNA-based next-generation sequencing. For patients with TRK fusion cancer, TRK inhibition is an important therapeutic target. Following the FDA approval of the selective TRK inhibitor, larotrectinib, as well as the ongoing development of multi-kinase inhibitors with activity in TRK fusion cancer, testing for NTRK gene fusions should become part of the standard diagnostic process. In this review we discuss the biology of NTRK gene fusions, and we present a testing algorithm to aid detection of these gene fusions in clinical practice and guide treatment decisions.

scholarly journals Neurons interact with the microbiome: an evolutionary-informed perspective

Neuroforum ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Christoph Giez ◽  
Alexander Klimovich ◽  
Thomas C. G. Bosch
Keyword(s):  
Nervous System ◽  
Neural Circuits ◽  
Current Knowledge ◽  
System Development ◽  
Nervous System Development ◽  
Comprehensive Understanding ◽  
Strategic Model ◽  
Microbe Interactions ◽  
Host Microbe Interactions ◽  
And Function

Abstract Animals have evolved within the framework of microbes and are constantly exposed to diverse microbiota. Microbes colonize most, if not all, animal epithelia and influence the activity of many organs, including the nervous system. Therefore, any consideration on nervous system development and function in the absence of the recognition of microbes will be incomplete. Here, we review the current knowledge on the nervous systems of Hydra and its role in the host–microbiome communication. We show that recent advances in molecular and imaging methods are allowing a comprehensive understanding of the capacity of such a seemingly simple nervous system in the context of the metaorganism. We propose that the development, function and evolution of neural circuits must be considered in the context of host–microbe interactions and present Hydra as a strategic model system with great basic and translational relevance for neuroscience.

Endocannabinoid signals in the developmental programming of delayed-onset neuropsychiatric and metabolic illnesses

2013 ◽  
Vol 41 (6) ◽  
pp. 1569-1576 ◽  
Author(s):  
Erik Keimpema ◽  
Daniela Calvigioni ◽  
Tibor Harkany
Keyword(s):  
Prescription Drugs ◽  
Maternal Nutrition ◽  
System Development ◽  
Nervous System Development ◽  
Molecular Evidence ◽  
Critical Periods ◽  
Affected Offspring ◽  
Neuropsychiatric Diseases ◽  
Maternal Programming ◽  
And Function

It is increasingly recognized that maternal exposure to metabolic (nutritional) stimuli, infections, illicit or prescription drugs and environmental stressors during pregnancy can predispose affected offspring to developing devastating postnatal illnesses. If detrimental maternal stimuli coincide with critical periods of tissue production and organogenesis then they can permanently derail key cellular differentiation programs. Maternal programming can thus either provoke developmental failure directly (‘direct hit’) or introduce latent developmental errors that enable otherwise sub-threshold secondary stressors to manifest as disease (‘double hit’) postnatally. Accumulating evidence suggests that nervous system development is tightly controlled by maternal metabolic stimuli, and whose synaptic wiring and integrative capacity are adversely affected by dietary and hormonal challenges, infections or episodes of illicit drug use. Endocannabinoids, a family of signal lipids derived from polyunsaturated fatty acids, have been implicated in neuronal fate determination, the control of axonal growth, synaptogenesis and synaptic neurotransmission. Therefore the continuum and interdependence of endocannabinoid actions during the formation and function of synapses together with dynamic changes in focal and circulating endocannabinoid levels upon maternal nutritional imbalance suggest that endocannabinoids can execute the ‘reprogramming’ of specific neuronal networks. In the present paper, we review molecular evidence suggesting that maternal nutrition and metabolism during pregnancy can affect the formation and function of the hippocampus and hypothalamus by altering endocannabinoid signalling such that neuropsychiatric diseases and obesity respectively ensue in affected offspring. Moreover, we propose that the placenta, fetal adipose and nervous tissues interact via endocannabinoid signals. Thus endocannabinoids are hypothesized to act as a molecular substrate of maternal programming.

IHC versus FISH versus NGS to detect ALK gene rearrangement in NSCLC: all questions answered?

2021 ◽  
pp. jclinpath-2021-207408
Author(s):  
Ullas Batra ◽  
Shrinidhi Nathany ◽  
Mansi Sharma ◽  
Sunil Pasricha ◽  
Abhishek Bansal ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Molecular Subtype ◽  
Small Cell Lung Carcinoma ◽  
In Situ Hybridisation ◽  
Progression Free Survival ◽  
Fluorescence In Situ Hybridisation ◽  
Cell Lung Carcinoma ◽  
Anaplastic Lymphoma ◽  
Diagnostic Modalities ◽  
Custom Panel

AimsAnaplastic lymphoma kinase (ALK) rearranged non-small cell lung carcinoma (NSCLC) is a distinct molecular subtype and rapid approval of ALK tyrosine kinase inhibitors (TKIs) has necessitated rapid and sensitive diagnostic modalities for the detection of this alteration. Gene rearrangements can be identified using many techniques including fluorescence in situ hybridisation (FISH), reverse transcriptase-PCR, next-generation sequencing (NGS) and immunohistochemistry (IHC) for fusion oncoprotein expression. We aimed to determine the concordance between IHC, FISH and NGS for ALK biomarker detection, and determine differences in sensitivity, and survival outcomes.MethodsWe analysed the concordance between IHC using D5F3 monoclonal antibody, FISH (break-apart) and NGS using a custom panel containing 71 different ALK variants.ResultsAmong 71 cases included in this study, FISH was evaluable in 58 cases. The concordance of ALK IHC with FISH was 75.9% and that with NGS was 84.5%. The sensitivities of FISH and NGS were 75.6% and 87.5%, respectively. The median progression-free survival of ALK IHC-positive and FISH-negative group was 5.5 months and that of both positive was 9.97 months.ConclusionAlthough NGS offers a better throughput and visualisation, IHC still remains the quintessential screening tool in upfront diagnosis of ALK rearranged NSCLC.

scholarly journals Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

2019 ◽  
Vol 21 (1) ◽  
pp. 266 ◽  
Author(s):  
Gabriella Schiera ◽  
Carlo Maria Di Liegro ◽  
Italia Di Liegro
Keyword(s):  
Learning And Memory ◽  
Extracellular Vesicles ◽  
Glial Cells ◽  
Information Exchange ◽  
System Development ◽  
Cell Communication ◽  
Nervous System Development ◽  
The Body ◽  
Pathological Conditions ◽  
And Function

Most aspects of nervous system development and function rely on the continuous crosstalk between neurons and the variegated universe of non-neuronal cells surrounding them. The most extraordinary property of this cellular community is its ability to undergo adaptive modifications in response to environmental cues originating from inside or outside the body. Such ability, known as neuronal plasticity, allows long-lasting modifications of the strength, composition and efficacy of the connections between neurons, which constitutes the biochemical base for learning and memory. Nerve cells communicate with each other through both wiring (synaptic) and volume transmission of signals. It is by now clear that glial cells, and in particular astrocytes, also play critical roles in both modes by releasing different kinds of molecules (e.g., D-serine secreted by astrocytes). On the other hand, neurons produce factors that can regulate the activity of glial cells, including their ability to release regulatory molecules. In the last fifteen years it has been demonstrated that both neurons and glial cells release extracellular vesicles (EVs) of different kinds, both in physiologic and pathological conditions. Here we discuss the possible involvement of EVs in the events underlying learning and memory, in both physiologic and pathological conditions.

Serotonergic gene variation: implications for personality traits and psychopathology

1999 ◽  
Vol 11 (2) ◽  
pp. 57-59
Author(s):  
K.P. Lesch
Keyword(s):  
Complex Traits ◽  
System Development ◽  
Brain Regions ◽  
Nervous System Development ◽  
Gene Variation ◽  
Serotonergic Activity ◽  
Neural Communication ◽  
Important Regulator ◽  
And Function ◽  
Master Control

Serotonin 5-hydroxytryptamine (5-HT) is an important regulator of morphogenetic activities during early central nervous system development, including cell proliferation, migration, and differentiation as well as synapto-genesis. Serotonergic raphe neurons diffusely project to a variety of brain regions (e.g. cortex, amygdala, hippocampus) and play known roles in integrating emotion, cognition, motor function as well as in food intake, sleep, pain, and sexual activity. The diversity of physiologic functions is due to the fact that 5-HT acts as a master control neurotransmitter within a highly complex system of neural communication mediated by multiple pre- and postsynaptic 5-HT receptors, thus orchestrating the activity and interaction of several other neurotransmitter systems. Since proteins involved in the regulation of central serotonergic activity (e.g. enzymes, receptors, transporter) play pivotal role in brain 5-HT homeostasis, polymorphisms in the regulatory regions of their genes resulting in variation of expression and function are likely to influence complex traits, such as temperament/personality and psychopathology.

scholarly journals A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function

2017 ◽  
Vol 39 (2) ◽  
pp. 187-192 ◽  
Author(s):  
Vincenzo Salpietro ◽  
Stephanie Efthymiou ◽  
Andreea Manole ◽  
Bhawana Maurya ◽  
Sarah Wiethoff ◽  
...  
Keyword(s):  
Nervous System ◽  
System Development ◽  
Rna Helicase ◽  
Nervous System Development ◽  
Homozygous Mutation ◽  
Loss Of Function ◽  
Dead Box ◽  
And Function

scholarly journals Synaptosome microRNAs regulate synapse functions in Alzheimer's disease

2021 ◽  
Author(s):  
Subodh Kumar ◽  
Erika Orlov ◽  
Prashanth Gowda ◽  
Chhanda Bose ◽  
Erika Orlov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
System Development ◽  
Microarray Platform ◽  
Nervous System Development ◽  
Cell Junction ◽  
Gabaergic Synapse ◽  
Unaffected Control ◽  
Postmortem Brains ◽  
And Function

MicroRNAs (miRNAs) are found in nerve terminals, synaptic vesicles, and synaptosomes, but it is unclear whether synaptic and cytosolic miRNA populations differ in Alzheimer's disease (AD) or if synaptosomal miRNAs affect AD synapse activity. To address these questions, we generated synaptosomes and cytosolic fractions from postmortem brains of AD and unaffected control (UC) samples and analyzed them using a global Affymetrix miRNAs microarray platform. A group of miRNAs significantly differed (p<0.0001) with high fold changes variance (+/- >200-fold) in their expressions in different comparisons- 1) UC synaptosome vs UC cytosol, 2) AD synaptosomes vs AD cytosol, 3) AD cytosol vs UC cytosol, and 4) AD synaptosomes vs UC synaptosomes. MiRNAs data analysis revealed that some potential miRNAs were consistently different across sample groups. These differentially expressed miRNAs were further validated using AD postmortem brains, brains of APP transgenic (Tg2576), Tau transgenic (P301L), and wild-type mice. The miR-501-3p, miR-502-3p and miR-877-5p were identified as potential synaptosomal miRNAs upregulated with disease progression based on AD Braak stages. Gene Ontology Enrichment and Ingenuity Pathway Analysis of synaptosomal miRNAs showed the involvement of miRNAs in nervous system development, cell junction organization, synapse assembly formation, and function of GABAergic synapse. This is the first description of synaptic versus cytosolic miRNAs in AD and their significance in synapse function.

scholarly journals Genetic Basis of Variation in Cocaine and Methamphetamine Consumption in Outbred Populations of Drosophila melanogaster

2021 ◽  
Author(s):  
Brandon M. Baker ◽  
Mary Anna Carbone ◽  
Wen Huang ◽  
Robert R. H. Anholt ◽  
Trudy F. C. Mackay
Keyword(s):  
Nervous System ◽  
Drosophila Melanogaster ◽  
Genetic Basis ◽  
Genetic Model ◽  
System Development ◽  
Gene Interaction ◽  
Nervous System Development ◽  
Drug Consumption ◽  
Human Populations ◽  
And Function

AbstractWe used Drosophila melanogaster to map the genetic basis of naturally occurring variation in voluntary consumption of cocaine and methamphetamine. We derived an outbred advanced intercross population (AIP) from 37 sequenced inbred wild-derived lines of the Drosophila melanogaster Genetic Reference Panel (DGRP), which are maximally genetically divergent, have minimal residual heterozygosity, are not segregating for common inversions, and are not infected with Wolbachia pipientis. We assessed consumption of sucrose, methamphetamine-supplemented sucrose and cocaine-supplemented sucrose, and found considerable phenotypic variation for consumption of both drugs, in both sexes. We performed whole genome sequencing and extreme QTL mapping on the top 10% of consumers for each replicate, sex and condition, and an equal number of randomly selected flies. We evaluated changes in allele frequencies among high consumers and control flies and identified 3,033 variants significantly (P < 1.9 × 10-8) associated with increased consumption, located in or near 1,962 genes. Many of these genes are associated with nervous system development and function, and 77 belong to a known gene-gene interaction subnetwork. We assessed the effects of RNA interference (RNAi) on drug consumption for 22 candidate genes; 17 had a significant effect in at least one sex. We constructed allele-specific AIPs which were homozygous for alternative candidate alleles for 10 SNPs and measured average consumption for each population; nine SNPs had significant effects in at least one sex. The genetic basis of voluntary drug consumption in Drosophila is polygenic and implicates genes with human orthologs and associated variants with sex- and drug-specific effects.Significance StatementThe use of cocaine and methamphetamine presents significant socioeconomic problems. However, identifying the genetic underpinnings that determine susceptibility to substance use is challenging in human populations. The fruit fly, Drosophila melanogaster, presents a powerful genetic model since we can control the genetic background and environment, 75% of disease-causing genes in humans have a fly counterpart, and flies - like humans - exhibit adverse effects upon cocaine and methamphetamine exposure. We showed that the genetic architecture underlying variation in voluntary cocaine and methamphetamine consumption differs between sexes and is dominated by variants in genes associated with connectivity and function of the nervous system. Results obtained from the Drosophila gene discovery model can guide studies on substance abuse susceptibility in human populations.

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