Scholar : ΣΤΟΜΑΤΙΤΙΣ - νέα αποτελέσματ

A Dramatic Case of Odynophagia

B Sopeña, J Limeres, L García-Caballero… - Dysphagia, 2017

… Recurrent necrotizing major aphthous stomatitis (Sutton's disease) is a clinical variant
of recurrent aphthous stomatitis that may have a dramatic course. Unfortunately, the lack
of etiopatho- genetic uniformity precludes any specific treatment …

Mouth

RE Phillips - The Physical Exam, 2018

… Aphthous Stomatitis. Perhaps the most common oral lesion, the canker sore is an ulcer that
appears over a day or 2. Notoriously painful, it goes away in 7–10 days … 15.2 Lichen planus.
Mycotic Stomatitis. Oral thrush is a fungal infection from Candida albicans …

[HTML] Frequencies of abnormal humoral and cellular immune component levels in peripheral blood of patients with recurrent aphthous ulceration

HH Ruan, GY Li, N Duan, HL Jiang, YF Fu, YF Song… - Journal of Dental Sciences, 2017

… The relationship between humoral and cellular immune may be potentially important immunologic
aspects involved in the pathogenesis of RAU. Keywords. stomatitis; aphthous; humoral immune;
cellular immune; immunoglobulins; lymphocytes. Introduction …

Recurrent Aphthous Stomatitis: An Assessment of Antioxidant Levels in Plasma and Saliva.

JS JESIJA, S GOPAL, HP SKIEL - Journal of Clinical & Diagnostic Research, 2017

Abstract Introduction: Recurrent Aphthous Stomatitis (RAS) is a common oral mucosal
disorder that affects 20% of the population worldwide. Factors such as trauma, stress,
genetic, hypersensitivity, nutrition, immune disturbance and hormonal imbalance may

[PDF] ASUHAN KEPERAWATAN PADA ANAK DENGAN DENGUE HAEMORRHAGIC FEVER (DHF) DI RSU DR. WAHIDIN SUDIRO

DR Sari - KTI D3 KEPERAWATAN, 2017

… Pemeriksaan fisik ditemukan ptekie, klien tampak lemas, perdarahan gusi dan stomatitis pada
lidah, nyeri pada perut bagian atas, pada pemeriksaan laboratorium didapatkan penurunan
trombosit 20 (10^3/uL). Responden 2 panas sejak 4 hari naik turun, mual muntah …

Comparative Study of Fusogenic Activity of H1 and H5 Subtypes Influenza Virus Hemagglutinins

AA Kononova, SV Cheresiz, AV Chechushkov… - Bulletin of Experimental …, 2017

… This could be due to different capsid sizes of influenza virus and ve- sicular stomatitis virus, which
determines their different permeability through the fusion pore … A vesicular stomatitis pseudovirus
expressing the surface glycoproteins of influenza A virus. Arch Virol …

[HTML] Diagnóstico clínico de pacientes con estomatitis subprótesis portadores de aparatología protésica

GAE Pereira, MM Filiu, LAA Despaigne - MEDISAN, 2017

… Clinical diagnosis of patients with subprosthesis stomatitis bearers of prosthetic aparatology.
Dra … Key words: subprosthesis stomatitis, prosthetics aparatology, dental prosthesis, loosened
prosthesis, continuous use of dental prosthesis, secondary health care. INTRODUCCIÓN …

[HTML] Lesiones bucales en adultos mayores y factores de riesgo. Policlínico" Dr. Tomás Romay", La Habana, Cuba

WM Páez, LV Loyola, YR Revilla, DLM González - Revista Habanera de Ciencias …, 2017

… the study were women, 24,8% aged 60-69 years, and 45,3% presented lesions which were more
frequently observed in the hard palate (62,9%) and the mucosa of the cheek (20,9%). Seven
kinds of buccal lesions were identified, with a priority of subprosthesis stomatitis (62,9 …

[HTML] Efficacy of Afatinib in a Previously-Treated Patient with Non-Small Cell Lung Cancer Harboring HER2 Mutation: Case Report

CK Park, JY Hur, CM Choi, TO Kim, HJ Cho, HJ Shin… - Journal of Korean Medical …, 2017

… neurologic symptom or sign. After stepwise dose reduction to 20 mg due to stomatitis
and nausea, she has continued the medication until February 2016 without
deterioration of subjective symptom and tumor burden. Last CT scan …

Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid …

T Seto, F Hirai, H Saka, Y Kogure, K Yoh, S Niho… - Japanese Journal of Clinical …, 2017

… Most frequent adverse events (AEs) included: vomiting, decreased appetite, diarrhea,
nausea and stomatitis (combination cohorts); gastrointestinal disorders, skin and
sub- cutaneous tissue disorders (monotherapy cohorts) …

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Scholar : ΟΓΚΟΛΟΓΙΑ - νέα αποτελέσματα

[PDF] Σύγχρονες θεραπευτικές προσεγγίσεις στον καρκίνο του παχέος εντέρου

Φ ΔΙΑΜΑΝΤΟΠΟΥΛΟΥ - 2017

… 38 5.2 Συμβολή νοσηλευτών ..... 39 Page 3. 3 5.3 Ογκολογία και
νοσηλευτής..... 40 5.4 Νοσηλευτής ογκολογικών ασθενών ..... 42 …

[PDF] Πολύποδες και αδενώματα παχέος εντέρου. Ορολογία, ιστοπαθολογία, πρόγνωση

Ε ΜΠΛΕΤΣΟΥ - 2017

… να μην μολυνθεί ο υγιής πληθυσμός. Τον 19ο αιώνα γεννήθηκε και η επιστημονική ογκολογία
μέσα από τη συστηματική πλέον χρήση του μικροσκοπίου και την ανάδυση της επιστήμης
της κυτταρικής παθολογίας από τον RudolfVirchow. Με αυτή …

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Scholar : ΑΚΟΗ - νέα αποτελέσματα

[PDF] Η γνωστική ψυχοκινητική και συναισθηματική επίδραση της μουσικής σε θεραπευτικά περιβάλλοντα αποκατάστασης και προαγωγής της υγείας

Α ΑΛΕΞΑΚΗ - 2017

… 1.2 Νευροφυσιολογία ακοής Η ακοή ειναι η αίσθηση που παράγεται όταν επιμήκεις δονήσεις
μορίων του … ανταλακλαστικών οι μουσικοί παρουσιάζουν για κάποιο λόγο ανθεκτικότητα στην
εκφύλιση των νευρωνικών δικτύων που εμπλέκονται στην ακοή και αντίληψη του ήχου …

[PDF] Αποτελεσματικότητα ομαδικής άσκησης στην τρίτη ηλικία

Σ Βαρούχα, Σ Νταουντάκη - 2017

… ουροποιητικό και το αναπαραγωγικό. Σημαντικές αλλαγές επίσης παρατηρούνται στα
αισθητικά συστήματα όπως στην όραση και την ακοή και σε γνωστικό επίπεδο όπως στην
μνήμη και την πνευματική λειτουργία. Οι βασικότερες αλλαγές …

[PDF] Μακράς δράσης αντιψυχωτική αγωγή σε ασθενείς με σχιζοφρένεια: Πλεονεκτήματα και μειονεκτήματα

Κ ΠΑΣΑΙ, Χ ΡΑΘΩΣΗ - 2017

Page 1. 1 Τεχνολογικό Εκπαιδευτικό Ίδρυ Τμήμα: Νοσηλ ΠΤΥΧΙΑΚΗ Ε "Μακράς δράσης
αντιψυχωτική σχιζοφρένεια: πλεονεκτήματα κ ΕΙΣΗΓΗΤΡΙΑ : ΣΟΥΜΠΑΣΗ ΕΥΑΝΘΙΑ
ΣΠΟΥΔΑΣΤΡΙΕΣ : ΠΑΣΑΙ ΚΛΙ ΡΑΘΩΣΗ ΧΡΙΣΤΙΝΑ γικό Εκπαιδευτικό Ίδρυμα Δυτικής Ελλάδας …

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Poland’s Syndrome: Are Postzygotic Mutations in β-Actin Associated with its Pathogenesis?

http://ift.tt/2iUfzIV

Expression of concern on 'The oldest hominin butchery in European mid-latitudes at the Jaramillo site of Untermassfeld (Thuringia, Germany)'

Publication date: Available online 13 November 2017
Source:Journal of Human Evolution





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Barrel Cortical Neuron Integrates Triple Associated Signals for Their Memory Through Receiving Epigenetic-Mediated New Synapse Innervations

Abstract

Associative learning is common way for information acquisition. Associative memory is essential to logical reasoning and associative thinking. The storages of multiple associated signals in individual neurons facilitate their integration, expand memory volume, and strengthen cognition ability. Associative memory cells that encode multiple signals have been reported, however, the mechanisms underlying their recruitment and working principle remain to be addressed. We have examined the recruitment of associative memory cells that integrate and store triple sensory signals as well as the potential mechanism of their recruitment. Paired mouse whisker, olfaction, and tail stimulations lead to odorant-induced motion and tail-induced whisker motion. In mice of expressing this cross-modal response, their barrel cortical neurons become to encode odor and tail signals alongside whisker signal. These barrel cortical neurons receive new synapse innervations from piriform and S1-tail cortical neurons. The emergence of cross-modal responses as well as the recruitments of new synapse innervations and associative memory cells in the barrel cortex need miRNA-324 and miRNA-133a, which downregulate Ttbk1 and Tet3. The co-activations of sensory cortices recruit their mutual synapse innervations and associative memory cells that integrate and store multiple associated signals through epigenetic-mediated process.

http://ift.tt/2mnwgl0

A Modulatory Effect of Brief Passive Exposure to Non-linguistic Sounds on Intrinsic Functional Connectivity: Relevance to Cognitive Performance

Abstract

A growing literature on resting-state fMRI (R-fMRI) has explored the impact of preceding sensory experience on intrinsic functional connectivity (iFC). However, it remains largely unknown how passive exposure to irrelevant auditory stimuli, which is a constant in everyday life, reconfigures iFC. Here, we directly compared pre- and post-exposure R-fMRI scans to examine: 1) modulatory effects of brief passive exposure to repeating non-linguistic sounds on subsequent iFC, and 2) associations between iFC modulations and cognitive abilities. We used an exploratory regional homogeneity (ReHo) approach that indexes local iFC, and performed a linear mixed-effects modeling analysis. A modulatory effect (increase) in ReHo was observed in the right superior parietal lobule (R.SPL) within the parietal attention network. Post hoc seed-based correlation analyses provided further evidence for increased parietal iFC (e.g., R.SPL with the right inferior parietal lobule). Notably, less iFC modulation was associated with better cognitive performance (e.g., word reading). These results suggest that: 1) the parietal attention network dynamically reconfigures its iFC in response to passive (thus irrelevant) non-linguistic sounds, but also 2) minimization of iFC modulation in the same network characterizes better cognitive performance. Our findings may open up new avenues for investigating cognitive disorders that involve impaired sensory processing.

http://ift.tt/2z0iE56

Shared and Disorder-Specific Neurocomputational Mechanisms of Decision-Making in Autism Spectrum Disorder and Obsessive-Compulsive Disorder

Abstract

Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) often share phenotypes of repetitive behaviors, possibly underpinned by abnormal decision-making. To compare neural correlates underlying decision-making between these disorders, brain activation of boys with ASD (N = 24), OCD (N = 20) and typically developing controls (N = 20) during gambling was compared, and computational modeling compared performance. Patients were unimpaired on number of risky decisions, but modeling showed that both patient groups had lower choice consistency and relied less on reinforcement learning compared to controls. ASD individuals had disorder-specific choice perseverance abnormalities compared to OCD individuals. Neurofunctionally, ASD and OCD boys shared dorsolateral/inferior frontal underactivation compared to controls during decision-making. During outcome anticipation, patients shared underactivation compared to controls in lateral inferior/orbitofrontal cortex and ventral striatum. During reward receipt, ASD boys had disorder-specific enhanced activation in inferior frontal/insular regions relative to OCD boys and controls. Results showed that ASD and OCD individuals shared decision-making strategies that differed from controls to achieve comparable performance to controls. Patients showed shared abnormalities in lateral-(orbito)fronto-striatal reward circuitry, but ASD boys had disorder-specific lateral inferior frontal/insular overactivation, suggesting that shared and disorder-specific mechanisms underpin decision-making in these disorders. Findings provide evidence for shared neurobiological substrates that could serve as possible future biomarkers.

http://ift.tt/2mpe5LL

Knockout Mice for Dyslexia Susceptibility Gene Homologs KIAA0319 and KIAA0319L have Unaffected Neuronal Migration but Display Abnormal Auditory Processing

Abstract

Developmental dyslexia is a neurodevelopmental disorder that affects reading ability caused by genetic and non-genetic factors. Amongst the susceptibility genes identified to date, KIAA0319 is a prime candidate. RNA-interference experiments in rats suggested its involvement in cortical migration but we could not confirm these findings in Kiaa0319-mutant mice. Given its homologous gene Kiaa0319L (AU040320) has also been proposed to play a role in neuronal migration, we interrogated whether absence of AU040320 alone or together with KIAA0319 affects migration in the developing brain. Analyses of AU040320 and double Kiaa0319;AU040320 knockouts (dKO) revealed no evidence for impaired cortical lamination, neuronal migration, neurogenesis or other anatomical abnormalities. However, dKO mice displayed an auditory deficit in a behavioral gap-in-noise detection task. In addition, recordings of click-evoked auditory brainstem responses revealed suprathreshold deficits in wave III amplitude in AU040320-KO mice, and more general deficits in dKOs. These findings suggest that absence of AU040320 disrupts firing and/or synchrony of activity in the auditory brainstem, while loss of both proteins might affect both peripheral and central auditory function. Overall, these results stand against the proposed role of KIAA0319 and AU040320 in neuronal migration and outline their relationship with deficits in the auditory system.

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Segregated Excitatory–Inhibitory Recurrent Subnetworks in Layer 5 of the Rat Frontal Cortex

Abstract

A prominent feature of neocortical pyramidal cells (PCs) is their numerous projections to diverse brain areas. In layer 5 (L5) of the rat frontal cortex, there are 2 major subtypes of PCs that differ in their long-range axonal projections, corticopontine (CPn) cells and crossed corticostriatal (CCS) cells. The outputs of these L5 PCs can be regulated by feedback inhibition from neighboring cortical GABAergic cells. Two major subtypes of GABAergic cells are parvalbumin (PV)-positive and somatostatin (SOM)-positive cells. PV cells have a fast-spiking (FS) firing pattern, while SOM cells have a low threshold spike (LTS) and regular spiking. In this study, we found that the 2 PC subtypes in L5 selectively make recurrent connections with LTS cells. The connection patterns correlated with the morphological and physiological diversity of LTS cells. LTS cells with high input resistance (Ri) exhibited more compact dendrites and more rebound spikes than LTS cells with low Ri, which had vertically elongated dendrites. LTS subgroups differently inhibited the PC subtypes, although FS cells made nonselective connections with both projection subtypes. These results demonstrate a novel recurrent network of inhibitory and projection-specific excitatory neurons within the neocortex.

http://ift.tt/2moQpau

Fractionating the Neurocognitive Mechanisms Underlying Working Memory: Independent Effects of Dopamine and Parkinson’s Disease

Abstract

Deficits in working memory (WM) in Parkinson's disease (PD) are often considered to be secondary to dopaminergic depletion. However, the neurocognitive mechanisms by which dopamine causes these deficits remain highly contested, and PD is now also known to be associated with nondopaminergic pathology. Here, we examined how PD and dopaminergic medication modulate three components of WM: maintenance over time, updating contents with new information and making memories distracter-resistant. Compared with controls, patients were disproportionately impaired when retaining information for longer durations. By applying a probabilistic model, we were able to reveal that the source of this error was selectively due to precision of memory representations degrading over time. By contrast, replenishing dopamine levels in PD improved executive control over both the ability to ignore and update, but did not affect maintenance of information across time. This was due to a decrease in guess responses, consistent with the view that dopamine serves to prevent WM representations being corrupted by irrelevant information, but has no impact on information decay. Cumulatively, these results reveal a dissociation in the neural mechanisms underlying poor WM: whereas dopamine reduces interference, nondopaminergic systems in PD appear to modulate processes that prevent information decaying more quickly over time.

http://ift.tt/2yZM9Ee

Optogenetic Modulation of a Minor Fraction of Parvalbumin-Positive Interneurons Specifically Affects Spatiotemporal Dynamics of Spontaneous and Sensory-Evoked Activity in Mouse Somatosensory Cortex in Vivo

Abstract

Parvalbumin (PV) positive interneurons exert strong effects on the neocortical excitatory network, but it remains unclear how they impact the spatiotemporal dynamics of sensory processing in the somatosensory cortex. Here, we characterized the effects of optogenetic inhibition and activation of PV interneurons on spontaneous and sensory-evoked activity in mouse barrel cortex in vivo. Inhibiting PV interneurons led to a broad-spectrum power increase both in spontaneous and sensory-evoked activity. Whisker-evoked responses were significantly increased within 20 ms after stimulus onset during inhibition of PV interneurons, demonstrating high temporal precision of PV-shaped inhibition. Multiunit activity was strongly enhanced in neighboring cortical columns, but not at the site of transduction, supporting a central and highly specific role of PV interneurons in lateral inhibition. Inversely, activating PV interneurons drastically decreased spontaneous and whisker-evoked activity in the principal column and exerted strong lateral inhibition. Histological assessment of transduced cells combined with quantitative modeling of light distribution and spike sorting revealed that only a minor fraction (~10%) of the local PV population comprising no more than a few hundred neurons is optogenetically modulated, mediating the observed prominent and widespread effects on neocortical processing.

http://ift.tt/2mpobMQ

Dysregulation of Cortical Neuron DNA Methylation Profile in Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) is a complex neuropsychiatric syndrome whose etiology includes genetic and environmental components. Since epigenetic marks are sensitive to environmental insult, they may be involved in the development of ASD. Initial brain studies have suggested a dysregulation of epigenetic marks in ASD. However, due to cellular heterogeneity in the brain, these studies have not determined if there is a true change in the neuronal epigenetic signature. Here, we report a genome-wide methylation study on fluorescence-activated cell sorting-sorted neuronal nuclei from the frontal cortex of 16 male ASD and 15 male control subjects. Using the 450 K BeadArray, we identified 58 differentially methylated regions (DMRs) that included loci associated to GABAergic system genes, particularly ABAT and GABBR1, and brain-specific MicroRNAs. Selected DMRs were validated by targeted Next Generation Bisulfite Sequencing. Weighted gene correlation network analysis detected 3 co-methylation modules which are significantly correlated to ASD that were enriched for genomic regions underlying neuronal, GABAergic, and immune system genes. Finally, we determined an overlap of the 58 ASD-related DMRs with neurodevelopment associated DMRs. This investigation identifies alterations in the DNA methylation pattern in ASD cortical neurons, providing further evidence that epigenetic alterations in disorder-relevant tissues may be involved in the biology of ASD.

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Pyramidal Cell Subtypes and Their Synaptic Connections in Layer 5 of Rat Frontal Cortex

Abstract

The frontal cortical areas make a coordinated response that generates appropriate behavior commands, using individual local circuits with corticostriatal and corticocortical connections in longer time scales than sensory areas. In secondary motor cortex (M2), situated between the prefrontal and primary motor areas, major subtypes of layer 5 corticostriatal cells are crossed-corticostriatal (CCS) cells innervating both sides of striatum, and corticopontine (CPn) cells projecting to the ipsilateral striatum and pontine nuclei. CCS cells innervate CPn cells unidirectionally: the former are therefore hierarchically higher than the latter among L5 corticostriatal cells. CCS cells project directly to both frontal and nonfrontal areas. On the other hand, CPn cells innervate the thalamus and layer 1a of frontal areas, where thalamic fibers relaying basal ganglia outputs are distributed. Thus, CCS cells can make activities of frontal areas in concert with those of nonfrontal area using corticocortical loops, whereas CPn cells are more involved in closed corticostriatal loops than CCS cells. Since reciprocal connections between CPn cells with facilitatory synapses may be related to persistent activity, CPn cells play a key role of longer time constant processes in corticostriatal as well as in corticocortical loops between the frontal areas.

http://ift.tt/2mpDcxZ

Visual Cortex Limits Pop-Out in the Superior Colliculus of Awake Mice

Abstract

We detect objects more readily if they differ from their surroundings in motion, color, or texture. This increased saliency is thought to be related to increased responses in the visual cortex. The superior colliculus is another brain area involved in vision and especially in directing gaze and attention. In this study, we show that differences in texture orientation also increase responses in the superficial layers of the superior colliculus that receive retinal and cortical input. We found that gratings evoke more neural response when surrounded by orthogonal gratings than when surrounded by parallel gratings, particularly in the awake mouse. This pop-out is not originating from the visual cortex, and silencing visual cortex increased the relative difference in response. A model shows that this can result from retinotopically matched excitation from visual cortex to the superior colliculus. We suggest that the perceptual saliency of a stimulus differing from its surround in a low-level feature like grating orientation could depend on visual processing in the superior colliculus.

http://ift.tt/2yYYQPJ

Optogenetic Activation of the Sensorimotor Cortex Reveals “Local Inhibitory and Global Excitatory” Inputs to the Basal Ganglia

Abstract

To understand how information from different cortical areas is integrated and processed through the cortico-basal ganglia pathways, we used optogenetics to systematically stimulate the sensorimotor cortex and examined basal ganglia activity. We utilized Thy1-ChR2-YFP transgenic mice, in which channelrhodopsin 2 is robustly expressed in layer V pyramidal neurons. We applied light spots to the sensorimotor cortex in a grid pattern and examined neuronal responses in the globus pallidus (GP) and entopeduncular nucleus (EPN), which are the relay and output nuclei of the basal ganglia, respectively. Light stimulation typically induced a triphasic response composed of early excitation, inhibition, and late excitation in GP/EPN neurons. Other response patterns lacking 1 or 2 of the components were also observed. The distribution of the cortical sites whose stimulation induced a triphasic response was confined, whereas stimulation of the large surrounding areas induced early and late excitation without inhibition. Our results suggest that cortical inputs to the GP/EPN are organized in a "local inhibitory and global excitatory" manner. Such organization seems to be the neuronal basis for information processing through the cortico-basal ganglia pathways, that is, releasing and terminating necessary information at an appropriate timing, while simultaneously suppressing other unnecessary information.

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The Tbr2 Molecular Network Controls Cortical Neuronal Differentiation Through Complementary Genetic and Epigenetic Pathways

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Neural Progenitor Cells in Cerebral Cortex of Epilepsy Patients do not Originate from Astrocytes Expressing GLAST

Abstract

Adult neurogenesis in human brain is known to occur in the hippocampus, the subventricular zone, and the striatum. Neural progenitor cells (NPCs) were reported in the cortex of epilepsy patients; however, their identity is not known. Since astrocytes were proposed as the source of neural progenitors in both healthy and diseased brain, we tested the hypothesis that NPCs in the epileptic cortex originate from reactive, alternatively, de-differentiated astrocytes that express glutamate aspartate transporter (GLAST). We assessed the capacity to form neurospheres and the differentiation potential of cells dissociated from fresh cortical tissue from patients who underwent surgical treatment for pharmacologically intractable epilepsy. Neurospheres were generated from 57% of cases (8/14). Upon differentiation, the neurosphere cells gave rise to neurons, oligodendrocytes, and astrocytes. Sorting of dissociated cells showed that only cells negative for GLAST formed neurospheres. In conclusion, we show that cells with neural stem cell properties are present in brain cortex of epilepsy patients, and that these cells are not GLAST-positive astrocytes.

http://ift.tt/2mpxI6r

Heritability of the Effective Connectivity in the Resting-State Default Mode Network

Abstract

The default mode network (DMN) is thought to reflect endogenous neural activity, which is considered as one of the most intriguing phenomena in cognitive neuroscience. Previous studies have found that key regions within the DMN are highly interconnected. Here, we characterized the genetic influences on causal or directed information flow within the DMN during the resting state. In this study, we recruited 46 pairs of twins and collected fMRI imaging data using a 3.0 T scanner. Dynamic causal modeling was conducted for each participant, and a structural equation model was used to calculate the heritability of DMN in terms of its effective connectivity. Model comparison favored a full-connected model. Structural equal modeling was used to estimate the additive genetics (A), common environment (C) and unique environment (E) contributions to variance for the DMN effective connectivity. The ACE model was preferred in the comparison of structural equation models. Heritability of DMN effective connectivity was 0.54, suggesting that the genetic made a greater contribution to the effective connectivity within DMN. Establishing the heritability of default-mode effective connectivity endorses the use of resting-state networks as endophenotypes or intermediate phenotypes in the search for the genetic basis of psychiatric or neurological illnesses.

http://ift.tt/2z0i2N6

Migration Pathways of Thalamic Neurons and Development of Thalamocortical Connections in Humans Revealed by Diffusion MR Tractography

Abstract

The thalamus plays an important role in signal relays in the brain, with thalamocortical (TC) neuronal pathways linked to various sensory/cognitive functions. In this study, we aimed to see fetal and postnatal development of the thalamus including neuronal migration to the thalamus and the emergence/maturation of the TC pathways. Pathways from/to the thalami of human postmortem fetuses and in vivo subjects ranging from newborns to adults with no neurological histories were studied using high angular resolution diffusion MR imaging (HARDI) tractography. Pathways likely linked to neuronal migration from the ventricular zone and ganglionic eminence (GE) to the thalami were both successfully detected. Between the ventricular zone and thalami, more tractography pathways were found in anterior compared with posterior regions, which was well in agreement with postnatal observations that the anterior TC segment had more tract count and volume than the posterior segment. Three different pathways likely linked to neuronal migration from the GE to the thalami were detected. No hemispheric asymmetry of the TC pathways was quantitatively observed during development. These results suggest that HARDI tractography is useful to identify multiple differential neuronal migration pathways in human brains, and regional differences in brain development in fetal ages persisted in postnatal development.

http://ift.tt/2moPmYb

Trajectory of Parvalbumin Cell Impairment and Loss of Cortical Inhibition in Traumatic Brain Injury

Abstract

Many neuropsychiatric symptoms that follow traumatic brain injury (TBI), including mood disorders, sleep disturbance, chronic pain, and posttraumatic epilepsy (PTE) are attributable to compromised cortical inhibition. However, the temporal trajectory of cortical inhibition loss and its underlying mechanisms are not known. Using paired-pulse transcranial magnetic stimulation (ppTMS) and immunohistochemistry, we tracked functional and cellular changes of cortical inhibitory network elements after fluid-percussion injury (FPI) in rats. ppTMS revealed a progressive loss of cortical inhibition as early as 2 weeks after FPI. This profile paralleled the increasing levels of cortical oxidative stress, which was accompanied by a gradual loss of parvalbumin (PV) immunoreactivity in perilesional cortex. Preceding the PV loss, we identified a degradation of the perineuronal net (PNN)—a specialized extracellular structure enwrapping cortical PV-positive (PV+) inhibitory interneurons which binds the PV+ cell maintenance factor, Otx2. The trajectory of these impairments underlies the reduced inhibitory tone, which can contribute to posttraumatic neurological conditions, such as PTE. Taken together, our results highlight the use of ppTMS as a biomarker to track the course of cortical inhibitory dysfunction post-TBI. Moreover, the neuroprotective role of PNNs on PV+ cell function suggests antioxidant treatment or Otx2 enhancement as a promising prophylaxis for post-TBI symptoms.

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The DNA Methyltransferase 1 (DNMT1) Controls the Shape and Dynamics of Migrating POA-Derived Interneurons Fated for the Murine Cerebral Cortex

Abstract

The proliferative niches in the subpallium generate a rich cellular variety fated for diverse telencephalic regions. The embryonic preoptic area (POA) represents one of these domains giving rise to the pool of cortical GABAergic interneurons and glial cells, in addition to striatal and residual POA cells. The migration from sites of origin within the subpallium to the distant targets like the cerebral cortex, accomplished by the adoption and maintenance of a particular migratory morphology, is a critical step during interneuron development. To identify factors orchestrating this process, we performed single-cell transcriptome analysis and detected Dnmt1 expression in murine migratory GABAergic POA-derived cells. Deletion of Dnmt1 in postmitotic immature cells of the POA caused defective migration and severely diminished adult cortical interneuron numbers. We found that DNA methyltransferase 1 (DNMT1) preserves the migratory shape in part through negative regulation of Pak6, which stimulates neuritogenesis at postmigratory stages. Our data underline the importance of DNMT1 for the migration of POA-derived cells including cortical interneurons.

http://ift.tt/2mpDfd9

Activity-Dependent Neuroplasticity Induced by an Enriched Environment Reverses Cognitive Deficits in Scribble Deficient Mouse

Abstract

Planar cell polarity (PCP) signaling is well known to play a critical role during prenatal brain development; whether it plays specific roles at postnatal stages remains rather unknown. Here, we investigated the role of a key PCP-associated gene scrib in CA1 hippocampal structure and function at postnatal stages. We found that Scrib is required for learning and memory consolidation in the Morris water maze as well as synaptic maturation and NMDAR-dependent bidirectional plasticity. Furthermore, we unveiled a direct molecular interaction between Scrib and PP1/PP2A phosphatases whose levels were decreased in postsynaptic density of conditional knock-out mice. Remarkably, exposure to enriched environment (EE) preserved memory formation in CaMK-Scrib^−/− mice by recovering synaptic plasticity and maturation. Thus, Scrib is required for synaptic function involved in memory formation and EE has beneficiary therapeutic effects. Our results demonstrate a distinct new role for a PCP-associated protein, beyond embryonic development, in cognitive functions during adulthood.

http://ift.tt/2z0i2g4

Sequential Firing Codes for Time in Rodent Medial Prefrontal Cortex

Abstract

A subset of hippocampal neurons, known as "time cells" fire sequentially for circumscribed periods of time within a delay interval. We investigated whether medial prefrontal cortex (mPFC) also contains time cells and whether their qualitative properties differ from those in the hippocampus and striatum. We studied the firing correlates of neurons in the rodent mPFC during a temporal discrimination task. On each trial, the animals waited for a few seconds in the stem of a T-maze. A subpopulation of units fired in a sequence consistently across trials for a circumscribed period during the delay interval. These sequentially activated time cells showed temporal accuracy that decreased as time passed as measured by both the width of their firing fields and the number of cells that fired at a particular part of the interval. The firing dynamics of the time cells was significantly better explained with the elapse of time than with the animals' position and velocity. The findings observed here in the mPFC are consistent with those previously reported in the hippocampus and striatum, suggesting that the sequentially activated time cells are not specific to these areas, but are part of a common representational motif across regions.

http://ift.tt/2mlWbto

Distinct Cerebellar Contributions to Cognitive-Perceptual Dynamics During Natural Viewing

Abstract

The crucial role of the cerebellum in motor learning and coordination is very well known. Considerable interest has recently shifted toward its contribution to nonmotor tasks, such as working memory, emotion, and language. However, the cognitive role and functional subdivisions of the cerebellum, particularly in dynamic, ecologically realistic contexts, are not yet established. By analyzing functional neuroimaging data acquired while participants viewed a short dramatic movie, we found that posterior and inferior cerebellar regions are reliably engaged in dynamic perceptual and affective processes with no explicit motor component. These cerebellar regions show significant relevance to visual salience and unexpected turning points of the movie. Our results demonstrate that distinct functional subdivisions of the cerebellum are robustly engaged in real-life cognitive processes, playing specific roles through a dynamic interaction with higher order regions in the cerebral cortex.

http://ift.tt/2hy0YWX

Automatic delineation of brain regions on MRI and PET images from the pig

Publication date: Available online 13 November 2017
Source:Journal of Neuroscience Methods
Author(s): Jonas Villadsen, Hanne D. Hansen, Louise M. Jørgensen, Sune H. Keller, Flemming L. Andersen, Ida N. Petersen, Gitte M. Knudsen, Claus Svarer
BackgroundThe increasing use of the pig as a research model in neuroimaging requires standardized processing tools. For example, extraction of regional dynamic time series from brain PET images requires parcellation procedures that benefit from being automated.Comparison with existing methodsManual inter-modality spatial normalization to a MRI atlas is operator-dependent, time-consuming, and can be inaccurate with lack of cortical radiotracer binding or skull uptake.New methodA parcellated PET template that allows for automatic spatial normalization to PET images of any radiotracer.ResultsMRI and [¹¹C]Cimbi-36 PET scans obtained in sixteen pigs made the basis for the atlas. The high resolution MRI scans allowed for creation of an accurately averaged MRI template. By aligning the within-subject PET scans to their MRI counterparts, an averaged PET template was created in the same space. We developed an automatic procedure for spatial normalization of the averaged PET template to new PET images and hereby facilitated transfer of the atlas regional parcellation. Evaluation of the automatic spatial normalization procedure found the median voxel displacement to be 0.22±0.08mm using the MRI template with individual MRI images and 0.92±0.26mm using the PET template with individual [¹¹C]Cimbi-36 PET images. We tested the automatic procedure by assessing eleven PET radiotracers with different kinetics and spatial distributions by using perfusion-weighted images of early PET time frames.ConclusionWe here present an automatic procedure for accurate and reproducible spatial normalization and parcellation of pig PET images of any radiotracer with reasonable blood-brain barrier penetration.



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Calcium imaging method to visualize the spatial patterns of neural responses in the pygmy squid, Idiosepius paradoxus, central nervous system

Publication date: Available online 13 November 2017
Source:Journal of Neuroscience Methods
Author(s): Motoki Koizumi, Shuichi Shigeno, Makoto Mizunami, Nobuaki K. Tanaka
BackgroundCephalopods exhibit unique behaviors such as camouflage and tactile learning. The brain functions correlated to these behaviors have long been analyzed through behavioral observations of animals subject to surgical manipulation or electrical stimulation of brain lobes. However, physiological methods have rarely been introduced to investigate the functions of each individual lobe, though physiological work on giant axons and slices of the vertical lobe system of the cephalopods have provided deep insights into ion conductance of nerves and long-term synaptic plasticity. The lack of in vivo physiological work is partly due to difficulties in immobilizing the brain which is contained within the soft body and applying calcium indicators to the cephalopod central nervous system.New methodWe here present a calcium imaging method to visualize neural responses in the central nervous system of the smallest squid, Idiosepius paradoxus.ResultsWe injected calcium indicator Cal-520 into the brachial lobes and revealed a spatiotemporal pattern of neural responses to the electrical stimulations of the axial nerve cord in the first arm.Comparison with existingmethods We established a method to immobilize the central nervous system which is contained within the soft body and record the calcium responses from the intact central nervous system.ConclusionsOur method provides a novel approach to investigate the mechanisms of how the characteristic organization of the cephalopod brain functions to induce their unique behaviors.



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Effects of primary care physician density, urologist presence, and insurance status on stage of diagnosis for urologic malignancies

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): Kristy D. Nguyen, Zain Z. Hyder, Marshall D. Shaw, Sarah B. Maness, Michael S. Cookson, Sanjay G. Patel, Kelly L. Stratton
ObjectiveTo evaluate effects of PCP density, insurance status, and urologist presence on stage of diagnosis for urologic malignancies. Cancer stage at diagnosis is an important outcome predictor. Studies have shown an inverse relationship to primary care physician (PCP) density and insurance coverage with stage of cancer diagnosis.MethodsData was obtained from OK2Share, an Oklahoma Central Cancer Registry, for bladder, kidney, and prostate cancer from 2000 to 2010. Physician data was obtained through the State Licensing Board. The 2010 national census was used for population data. High PCP density was defined as greater than or equal to the median value: 3.17 PCP/10,000 persons. Chi-square and multivariate logistic regressions were used to analyze effects of PCP density, insurance status, and urologist presence on advanced stage diagnosis.Results27,086 patients were identified across 77 counties. As PCP density increased by 1 PCP/10,000 persons, the odds ratios (OR) of an advanced stage at diagnosis were 0.383, 0.468, 0.543 for bladder, kidney, and prostate cancer respectively. Compared to private insurance, being uninsured had OR of 1.61 and 2.45 respectively for kidney and prostate cancers. The OR of an advanced stage diagnosis for bladder and prostate cancer were 3.77 and 1.73, respectively, in counties with a urologist.ConclusionsIncreased PCP density and insurance coverage reduced the odds of an advanced diagnosis. Implementation of policies to improve access to healthcare including through increasing PCP density and reducing the number of uninsured patients should result in diagnosis at an earlier stage, which will likely improved cancer-related outcomes.



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Radiobiology and radiotherapy of brain metastases

Abstract

Brain metastases are the most common intracranial tumors in adults, accounting for more than 50% of all such cases. The approach to and management of brain metastases have evolved significantly in recent years due to several reasons. These include advances in neurosurgical and radiotherapeutic techniques, improved systemic therapy options offering better systemic and intracranial disease control and prolongation of survival as a result of these improvements, making side-effects of proposed therapies (e.g. neurocognitive decline from whole brain radiotherapy) an important consideration. In this article, we review the the primary therapeutic approaches to the management of brain metastases, namely, surgery, stereotactic radiosurgery, and whole brain radiation therapy and the primary factors dictating choice.

http://ift.tt/2jpXTJd

Excessive use of nitrogenous fertilizers: an unawareness causing serious threats to environment and human health

Abstract

Farmers occasionally need to add nitrogen fertilizer to their farms and gardens to make available just the precise nutrients for their plants' growth. The applications of inorganic nitrogen fertilizers to various crops have been continuously increasing since last many decades globally. Although nitrogen fertilizer contributes substantially to yield enhancement, but excessive use of this manure has posed serious threats to environment and human health. Rate of nitrogen fertilizers application has a close relationship with nitrate accumulation in surrounding environment, groundwater, as well as leafy and root vegetables. Consumption of diets having high nitrate contents has contributed to endogenous nitrosation, which could lead to thyroid condition, various kinds of human cancers, neural tube defects (during fetus development), and diabetes. In this short review, the authors have tried to create awareness among general public, farming community, health practitioners, and agricultural scientists for the risk involved with excessive use of nitrogen fertilizers to human health. Carcinogenic activity and other adverse effects of N-nitroso compounds might be prevented by consuming vitamin C and antioxidants containing fruits and vegetables.

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Reported Mistreatment During the Surgery Clerkship Varies by Student Career Choice

Publication date: Available online 13 November 2017
Source:Journal of Surgical Education
Author(s): Michael T. Kemp, Margaret Smith, Scott Kizy, Michael Englesbe, Rishindra M. Reddy
BackgroundStudent mistreatment is often a major concern during the surgery clerkship. We hypothesized that mistreatment is decreasing and that career choice may reflect perceived mistreatment.MethodsWe surveyed 2319 physicians about their surgery clerkships. Mistreatment reporting was correlated to physician specialty and medical school graduation year.ResultsThe response rate was 18.9% (440/2319). Recent graduates reported less mistreatment than more senior graduates (24.3%-50%, p = 0.0198). General surgeons (3/31, 9%), neurologists (1/7, 14%), and subspecialty surgeons (8/35, 19%) reported the lowest mistreatment rates. Psychiatrists (9/16, 56%), internists (31/69, 45%), pathologists (5/13, 38%), and emergency physicians (5/14, 36%) reported the highest rates. The reported rate of mistreatment by nonsurgeons was higher than surgeons (30.4% versus 14.3%, p < 0.0046). Mistreatment included sexual harassment, verbal abuse, and lack of teaching.ConclusionsMistreatment during surgery appears to be improving. Its perception varies by the field of training, indicating variable interpretations of what constitutes mistreatment.



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Elimination and detoxification of 2,4-D by Umbelopsis isabellina with the involvement of cytochrome P450

Abstract

The chemical 2,4-dichlorophenoxyacetic acid (2,4-D) is used in agriculture as a herbicide. Its intensive use has an adverse effect on the environment. This study involved examining the degradation of 2,4-D compound by the filamentous fungus Umbelopsis isabellina. After 5 days of incubation, 98% of the herbicide (added at 25 mg L⁻¹) was found to be removed. The elimination of 2,4-D by U. isabellina was connected with the formation of 2,4-dichlorophenol (2,4-DCP), which resulted in a 60% decrease in the sample toxicity toward Artemia franciscana larvae. The metabolism of 2,4-D was inhibited by the addition of metyrapone, a known cytochrome P450 inhibitor. It provides evidence that cytochrome P450 system is involved in 2,4-D metabolism in U. isabellina.

http://ift.tt/2zVAlTL

Correction to: Economic growth and CO 2 emissions: an investigation with smooth transition autoregressive distributed lag models for the 1800–2014 period in the USA

Abstract

The original publication of this paper contains a mistake.

http://ift.tt/2zCdVpG

A Two-Faced mSWI/SNF Subunit: Dual Roles for ARID1A in Tumor Suppression and Oncogenicity in the Liver

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Jordan E. Otto, Cigall Kadoch
In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit ARID1A in the development and progression of hepatocellular carcinoma (HCC).

Teaser

In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit, ARID1A, in the development and progression of hepatocellular carcinoma (HCC).


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Early GalNAc O-Glycosylation: Pushing the Tumor Boundaries

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Joana Gomes, Stefan Mereiter, Ana Magalhães, Celso A. Reis
Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14.

Teaser

Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14.


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Does CSF1R Blockade Turn into Friendly Fire?

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Tim F. Greten
In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts.

Teaser

In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts.


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Pontine Infantile Glioma Simplified

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Vijay Ramaswamy, Michael D. Taylor
In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer.

Teaser

In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer.


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Molecular Landscape of Non-Muscle Invasive Bladder Cancer

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Joshua J. Meeks, Seth P. Lerner
In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations.

Teaser

In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling and increased risk of recurrence. Tumors from female patients have a higher frequency of KDM6A mutations.


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Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): John D. Hayes, Albena T. Dinkova-Kostova
In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.

Teaser

In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.


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Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Hugues de Thé, Pier Paolo Pandolfi, Zhu Chen
Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.

Teaser

Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.


http://ift.tt/2AJptFG

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Xuxu Sun, Sam C. Wang, Yonglong Wei, Xin Luo, Yuemeng Jia, Lin Li, Purva Gopal, Min Zhu, Ibrahim Nassour, Jen-Chieh Chuang, Thomas Maples, Cemre Celen, Liem H. Nguyen, Linwei Wu, Shunjun Fu, Weiping Li, Lijian Hui, Feng Tian, Yuan Ji, Shuyuan Zhang, Mahsa Sorouri, Tae Hyun Hwang, Lynda Letzig, Laura James, Zixi Wang, Adam C. Yopp, Amit G. Singal, Hao Zhu
ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.

Graphical abstract

Teaser

Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.


http://ift.tt/2yz2fk6

Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Leire Bejarano, Alberto J. Schuhmacher, Marinela Méndez, Diego Megías, Carmen Blanco-Aparicio, Sonia Martínez, Joaquín Pastor, Massimo Squatrito, Maria A. Blasco
Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.

Graphical abstract

Teaser

Bejarano et al. show that genetic or chemical inhibition of TRF1 increases telomeric DNA damage and reduces proliferation and stemness independent of telomere length. TRF1 inhibition also inhibits glioblastoma initiation and progression and prolongs survival in genetic and xenograft glioblastoma models.


http://ift.tt/2yBI6df

A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Javier Robles-Valero, L. Francisco Lorenzo-Martín, Mauricio Menacho-Márquez, Isabel Fernández-Pisonero, Antonio Abad, Mireia Camós, María L. Toribio, Lluis Espinosa, Anna Bigas, Xosé R. Bustelo
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX⁺ clinical subtype, further underscoring the suppressor role of this pathway.

Graphical abstract

Teaser

Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX⁺ T-ALL.


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Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Anh Tuan Nguyen, Joanne Chia, Manon Ros, Kam Man Hui, Frederic Saltel, Frederic Bard
Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER.

Graphical abstract

Teaser

Nguyen et al. find that O-glycosylation increases during liver tumor progression, with increased expression of GALNT1 and glycosylation of ER-associated proteins. In mouse models, expression of GALNT1 in the ER, but not the Golgi, accelerates tumorigenesis and increases invasion through glycosylation of MMP14.


http://ift.tt/2yzhcCB

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Vinit Kumar, Laxminarasimha Donthireddy, Douglas Marvel, Thomas Condamine, Fang Wang, Sergio Lavilla-Alonso, Ayumi Hashimoto, Prashanthi Vonteddu, Reeti Behera, Marlee A. Goins, Charles Mulligan, Brian Nam, Neil Hockstein, Fred Denstman, Shanti Shakamuri, David W. Speicher, Ashani T. Weeraratna, Timothy Chao, Robert H. Vonderheide, Lucia R. Languino, Peter Ordentlich, Qin Liu, Xiaowei Xu, Albert Lo, Ellen Puré, Chunsheng Zhang, Andrey Loboda, Manuel A. Sepulveda, Linda A. Snyder, Dmitry I. Gabrilovich
Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.

Graphical abstract

Teaser

Kumar et al. show that CSF1R inhibition alters chemokine secretion by cancer-associated fibroblasts, which attracts pro-tumor PMN-MDSCs and results in poor efficacy. Combined inhibition of CSF1R and CXCR2 blocks MDSC recruitment and reduces tumor growth, which is further improved by the addition of anti-PD-1.


http://ift.tt/2yz28oG

An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Asis Palazon, Petros A. Tyrakis, David Macias, Pedro Veliça, Helene Rundqvist, Susan Fitzpatrick, Nikola Vojnovic, Anthony T. Phan, Niklas Loman, Ingrid Hedenfalk, Thomas Hatschek, John Lövrot, Theodoros Foukakis, Ananda W. Goldrath, Jonas Bergh, Randall S. Johnson
Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8⁺ T cells. Furthermore, loss of HIF-1α in CD8⁺ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8⁺ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8⁺ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity.

Teaser

Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8⁺ T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.


http://ift.tt/2yCxL0g

Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency

Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Carolyn D. Hurst, Olivia Alder, Fiona M. Platt, Alastair Droop, Lucy F. Stead, Julie E. Burns, George J. Burghel, Sunjay Jain, Leszek J. Klimczak, Helen Lindsay, Jo-An Roulson, Claire F. Taylor, Helene Thygesen, Angus J. Cameron, Anne J. Ridley, Helen R. Mott, Dmitry A. Gordenin, Margaret A. Knowles
Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.

Graphical abstract

Teaser

By analyzing 140 primary patient samples, Hurst et al. identify two genomic subtypes of stage Ta non-invasive bladder cancer. The more genomically unstable subtype is distinguished by loss of chromosome 9q sequences, upregulated mTORC1 signaling, and altered metabolic profile. They also find that females have a higher frequency of KDM6A mutations than males.


http://ift.tt/2AI13vW