Prognostic factors and patterns of locoregional failure after surgical resection in patients with cholangiocarcinoma without adjuvant radiation therapy: optimal field design for adjuvant radiation therapy

Publication date: Available online 5 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Zahra Ghiassi-Nejad, Paola Tarchi, Erin Moshier, Meng Ru, Parissa Tabrizian, Myron Schwartz, Michael Buckstein
PurposeTo identify prognostic factors and patterns of local failure in patients with cholangiocarcinoma, following surgical resection in the absence of adjuvant radiation, for optimal definition of target volumes encompassing the majority of local recurrences.Methods and MaterialsA chart review was performed in patients who underwent resection for primary CCA (intrahepatic, hilar, and distal) between 1999 and 2014. Local failure was defined as recurrence in a theoretical reasonable post-operative radiation volume. This includes the cut surface of liver, biliary anastomosis, hilum, portal nodes, celiac nodes, peri-pancreatic nodes, gastro-hepatic nodes, and retroperitoneal nodes. Patients who received adjuvant radiation were excluded.Results189 patients underwent surgical resection for CCA, of which 145 patients had sufficient follow up. Median follow up was 41.6 months (95% CI: 35.4-48.7). 102 cases were intrahepatic, and 43 were hilar/distal CCA. Adjuvant chemotherapy was given in 38 (26%) of cases, of which 20 (54%) were gemcitabine based. Eighty six patients (59%) had a documented recurrence, of which 44 (51%) had a locoregional component. Among patients that had a recurrence, 23 (27%) had a recurrence at the biliary anastomosis and/or cut liver surface. Twenty eight (32.6%) patients had a recurrence in the regional lymph nodes, most prevalent in the portal (16.3%), and retroperitoneal (17.4%) lymph nodes. Univariable analysis identified tumor size, any vascular invasion, presence of satellites, stage/nodal status and receipt of chemotherapy were significant prognostic factors of overall recurrence among IHC patients. Presence of satellites, and stage 3/Nx status remained statistically significant in multivariable modeling.ConclusionsThe areas at highest risk for locoregional recurrence following surgical resection are the biliary anastomosis/cut liver surface, portal lymph nodes, and retroperitoneal lymph nodes. While these results need to be validated, adjuvant radiation should possibly cover these areas to maximize locoregional control.

Teaser

Locoergional recurrences following surgical resection for cholangiocarcinoma (CCA) cause significant morbidity and mortality. This retrospective analysis explores risk factors for local failures and maps locoregional recurrences in patients who underwent surgery without adjuvant radiation. The recurrence map provides valuable information for delineating optimal planning target volumes for adjuvant radiation.


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A Complex Code of Extrinsic Influences on Cortical Progenitor Cells of Higher Mammals

Abstract

Development of the cerebral cortex depends critically on the regulation of progenitor cell proliferation and fate. Cortical progenitor cells are remarkably diverse with regard to their morphology as well as laminar and areal position. Extrinsic factors, such as thalamic axons, have been proposed to play key roles in progenitor cell regulation, but the diversity, extent and timing of interactions between extrinsic elements and each class of cortical progenitor cell in higher mammals remain undefined. Here we use the ferret to demonstrate the existence of a complex set of extrinsic elements that may interact, alone or in combination, with subpopulations of progenitor cells, defining a code of extrinsic influences. This code and its complexity vary significantly between developmental stages, layer of residence and morphology of progenitor cells. By analyzing the spatial-temporal overlap of progenitor cell subtypes with neuronal and axonal populations, we show that multiple sets of migrating neurons and axon tracts overlap extensively with subdivisions of the Subventricular Zones, in an exquisite lamina-specific pattern. Our findings provide a framework for understanding the feedback influence of both intra- and extra-cortical elements onto progenitor cells to modulate their dynamics and fate decisions in gyrencephalic brains.

http://ift.tt/2uN4cHe

Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD

Abstract

Fetal Alcohol Spectrum Disorders, or FASD, represent a range of adverse developmental conditions caused by prenatal ethanol exposure (PrEE) from maternal consumption of alcohol. PrEE induces neurobiological damage in the developing brain leading to cognitive-perceptual and behavioral deficits in the offspring. Alcohol-mediated alterations to epigenetic function may underlie PrEE-related brain dysfunction, with these changes potentially carried across generations to unexposed offspring. To determine the transgenerational impact of PrEE on neocortical development, we generated a mouse model of FASD and identified numerous stable phenotypes transmitted via the male germline to the unexposed third generation. These include alterations in ectopic intraneocortical connectivity, upregulation of neocortical Rzrβ and Id2 expression accompanied by both promoter hypomethylation of these genes and decreased global DNA methylation levels. DNMT expression was also suppressed in newborn PrEE cortex, providing further insight into how ethanol perturbs DNA methylation leading to altered regulation of gene transcription. These PrEE-induced, transgenerational phenotypes may be responsible for cognitive, sensorimotor, and behavioral deficits seen in humans with FASD. Thus, understanding the possible epigenetic mechanisms by which these phenotypes are generated may reveal novel targets for therapeutic intervention of FASD and lead to advances in human health.

http://ift.tt/2tOO4rw

fMRI-based Neuronal Response to New Odorants in the Newborn Brain

Abstract

The sense of smell is one of the oldest and the most primitive senses mammals possess, it helps to evaluate the surrounding environment. From birth, smell is an important sensory modality, highly relevant for neonatal behavioral adaptation. Even though human newborns seem to be able to perceive and react to olfactory stimuli, there is still a lack of knowledge about the ontogeny of smell and the underlying central processing involved in odor perception in newborns. Brain networks involved in chemosensory perception of odorants are well described in adults, however in newborns there is no evidence that central olfaction is functional given the largely unmyelinated neonatal central nervous system. To examine this question, we used functional magnetic resonance imaging (fMRI) in the newborn to characterize cortical response to olfactory and trigeminal odorants. Here we show that brain response to odors can be measured and localized using functional MRI in newborns. Furthermore, we found that the developing brain, only few days after birth, processes new artificial odorants in similar cortical areas than adults, including piriform cortex, orbitofrontal cortex and insula. Our work provides evidence that human olfaction at birth relies on brain functions that involve all levels of the cortical olfactory system.

http://ift.tt/2uMELFy

Effects of Adult Female Rat Androgenization on Brain Morphology and Metabolomic Profile

Abstract

Androgenization in adult natal women, as in transsexual men (TM), affects brain cortical thickness and the volume of subcortical structures. In order to understand the mechanism underlying these changes we have developed an adult female rat model of androgenization. Magnetic resonance imaging and spectroscopy were used to monitor brain volume changes, white matter microstructure and ex vivo metabolic profiles over 32 days in androgenized and control subjects. Supraphysiological doses of testosterone prevents aging decrease of fractional anisotropy values, decreased general cortical volume and the relative concentrations of glutamine (Gln) and myo-Inositol (mI). An increase in the N-acetylaspartate (NAA)/mI ratio was detected d. Since mI and Gln are astrocyte markers and osmolytes, we suspect that the anabolic effects of testosterone change astrocyte osmolarity so as to extrude Mi and Gln from these cells in order to maintain osmotic homeostasis. This mechanism could explain the brain changes observed in TM and other individuals receiving androgenic anabolic steroids.

http://ift.tt/2tOQwhQ

Parvalbumin-Positive Interneurons Regulate Neuronal Ensembles in Visual Cortex

Abstract

For efficient cortical processing, neural circuit dynamics must be spatially and temporally regulated with great precision. Although parvalbumin-positive (PV) interneurons can control network synchrony, it remains unclear how they contribute to spatio-temporal patterning of activity. We investigated this by optogenetic inactivation of PV cells with simultaneous two-photon Ca²⁺ imaging from populations of neurons in mouse visual cortex in vivo. For both spontaneous and visually evoked activity, PV interneuron inactivation decreased network synchrony. But, interestingly, the response reliability and spatial extent of coactive neuronal ensembles during visual stimulation were also disrupted by PV-cell suppression, which reduced the functional repertoire of ensembles. Thus, PV interneurons can control the spatio-temporal dynamics of multineuronal activity by functionally sculpting neuronal ensembles and making them more different from each other. In doing so, inhibitory circuits could help to orthogonalize multicellular patterns of activity, enabling neural circuits to more efficiently occupy a higher dimensional space of potential dynamics.

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Glibenclamide pretreatment protects against chronic memory dysfunction and glial activation in rat cranial blast traumatic brain injury

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Jesse A. Stokum, Kaspar Keledjian, Erik Hayman, Jason K. Karimy, Adam Pampori, Ziyan Imran, Seung Kyoon Woo, Volodymyr Gerzanich, J. Marc Simard
Blast traumatic brain injury (bTBI) affects both military and civilian populations, and often results in chronic deficits in cognition and memory. Chronic glial activation after bTBI has been linked with cognitive decline. Pharmacological inhibition of sulfonylurea receptor 1 (SUR1) with glibenclamide was shown previously to reduce glial activation and improve cognition in contusive models of CNS trauma, but has not been examined in bTBI. We postulated that glibenclamide would reduce chronic glial activation and improve long-term memory function after bTBI. Using a rat direct cranial model of bTBI (dc-bTBI), we evaluated the efficacy of two glibenclamide treatment paradigms: glibenclamide prophylaxis (pre-treatment), and treatment with glibenclamide starting after dc-bTBI (post-treatment). Our results show that dc-bTBI caused hippocampal astrocyte and microglial/macrophage activation that was associated with hippocampal memory dysfunction (rapid place learning paradigm) at 28days, and that glibenclamide pre-treatment, but not post-treatment, effectively protected against glial activation and memory dysfunction. We also report that a brief transient time-window of blood-brain barrier (BBB) disruption occurs after dc-bTBI, and we speculate that glibenclamide, which is mostly protein bound and does not normally traverse the intact BBB, can undergo CNS delivery only during this brief transient opening of the BBB. Together, our findings indicate that prophylactic glibenclamide treatment may help to protect against chronic cognitive sequelae of bTBI in warfighters and other at-risk populations.



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HBK-15 protects mice from stress-induced behavioral disturbances and changes in corticosterone, BDNF, and NGF levels

Publication date: 30 August 2017
Source:Behavioural Brain Research, Volume 333
Author(s): Karolina Pytka, Monika Głuch-Lutwin, Magdalena Kotańska, Elżbieta Żmudzka, Magdalena Jakubczyk, Anna Waszkielewicz, Paulina Janiszewska, Maria Walczak
Unlike majority of current antidepressants, HBK-15–a 5-HT1A and 5-HT7 receptor antagonist – showed memory-enhancing properties. In this study, we aimed to further characterize pharmacological profile of HBK-15 and investigate its antidepressant- and anxiolytic-like activity in the mouse model of unpredictable chronic mild stress. We used sucrose consumption test, forced swim test and elevated plus maze test as behavioral endpoints. We also evaluated the influence of HBK-15 on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus and prefrontal cortex, as well as body weight, relative adrenal glands weight and plasma corticosterone level in the stressed mice. We utilized LC/MS/MS method to determine HBK-15 concentration in plasma and brain. We evaluated pharmacokinetic profile and distribution to brain of HBK-15 (2.5mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration in CD-1 mice. HBK-15 (2.5mg/kg but not 1.25mg/kg) and fluoxetine (10mg/kg) protected stressed mice from anhedonic-, depressive- and anxiety-like behaviors, decreases in the BDNF and NGF levels in the hippocampus and prefrontal cortex, increases in plasma corticosterone levels and relative adrenal glands weight. The pharmacokinetic analysis demonstrated a rapid absorption of HBK-15 after i.p. administration (tmax=5min), a short half-life (t0.5=74min), large volume of distribution (Vss=3.7L/kg) and bioavailability after i.p. administration equal 25%. HBK-15 administered i.v. and i.p. significantly penetrated brain. Our results suggest that the blockade of serotonergic 5-HT1A and 5-HT7 receptors might be beneficial in the treatment of depressive disorders with cognitive dysfunction.



http://ift.tt/2uMLq2R

Neuromagnetic correlates of voice pitch, vowel type, and speaker size in auditory cortex

Publication date: September 2017
Source:NeuroImage, Volume 158
Author(s): Martin Andermann, Roy D. Patterson, Carolin Vogt, Lisa Winterstetter, André Rupp
Vowel recognition is largely immune to differences in speaker size despite the waveform differences associated with variation in speaker size. This has led to the suggestion that voice pitch and mean formant frequency (MFF) are extracted early in the hierarchy of hearing/speech processing and used to normalize the internal representation of vowel sounds. This paper presents a magnetoencephalographic (MEG) experiment designed to locate and compare neuromagnetic activity associated with voice pitch, MFF and vowel type in human auditory cortex. Sequences of six sustained vowels were used to contrast changes in the three components of vowel perception, and MEG responses to the changes were recorded from 25 participants. A staged procedure was employed to fit the MEG data with a source model having one bilateral pair of dipoles for each component of vowel perception. This dipole model showed that the activity associated with the three perceptual changes was functionally separable; the pitch source was located in Heschl's gyrus (bilaterally), while the vowel-type and formant-frequency sources were located (bilaterally) just behind Heschl's gyrus in planum temporale. The results confirm that vowel normalization begins in auditory cortex at an early point in the hierarchy of speech processing.



http://ift.tt/2tL6wla

Longitudinal changes in reading network connectivity related to skill improvement

Publication date: September 2017
Source:NeuroImage, Volume 158
Author(s): Jessica Wise Younger, Elliot Tucker-Drob, James R. Booth
Attempts to characterize the neural differences between individuals with and without dyslexia generally point to reduced activation in and connectivity between brain areas in a reading network composed of the inferior frontal gyrus, the ventral occipito-temporal cortex, and the dorsal temporo-parietal circuit. However, developmental work on brain activity during reading has indicated that some brain areas show developmental decreases in activation with age. Thus, reading network connectivity may also show decreases that are positively associated with increases in reading ability. However, the developmental trajectory of reading network connectivity in typically developing readers is not yet well established. In the current study, we use a longitudinal design to determine how connectivity changes over time, and how these changes relate to changes in reading skill. We find that longitudinal increases in reading ability are associated with higher initial connectivity in the dorsal stream between fusiform and inferior parietal cortex, implicated in phonological decoding, followed by decreases in connectivity in this stream over time. We further find that increases in reading ability are supported by maintenance of connectivity in the ventral stream between inferior occipital and fusiform cortex, suggesting a more mature automatic orthographic recognition strategy. Readers who show little reading improvement over time do not attain high levels of connectivity in the dorsal stream at any time point, and their ventral stream connectivity decreases over time. These results together suggest that superior reading ability is initially supported by phonological decoding, with a decreased reliance on this strategy as reading becomes more automated. Our results indicate that development of the dorsal and ventral streams are closely linked, and support the hypothesis that a decrease in the dorsal stream is important for ventral stream development.



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THIRD GENERATION EGFR TKIs IN EGFR-MUTATED NSCLC: WHERE ARE WE NOWAND WHERE ARE WE GOING

Publication date: Available online 5 July 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): A. Russo, T. Franchina, G.R.R. Ricciardi, V. Smiroldo, M. Picciotto, M. Zanghì, C. Rolfo, V. Adamo
The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.



http://ift.tt/2usUx9A

Recruitment of Staufen2 Enhances Dendritic Localization of an Intron-Containing CaMKIIα mRNA

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Raúl Ortiz, Maya V. Georgieva, Sara Gutiérrez, Neus Pedraza, Sandra M. Fernández-Moya, Carme Gallego
Regulation of mRNA localization is a conserved cellular process observed in many types of cells and organisms. Asymmetrical mRNA distribution plays a particularly important role in the nervous system, where local translation of localized mRNA represents a key mechanism in synaptic plasticity. CaMKIIα is a very abundant mRNA detected in neurites, consistent with its crucial role at glutamatergic synapses. Here, we report the presence of CaMKIIα mRNA isoforms that contain intron i16 in dendrites, RNA granules, and synaptoneurosomes from primary neurons and brain. This subpopulation of unspliced mRNA preferentially localizes to distal dendrites in a synaptic-activity-dependent manner. Staufen2, a well-established marker of RNA transport in dendrites, interacts with intron i16 sequences and enhances its distal dendritic localization, pointing to the existence of intron-mediated mechanisms in the molecular pathways that modulate dendritic transport and localization of synaptic mRNAs.

Graphical abstract

Teaser

Ortiz et al. have found that a subset of the total CaMKIIα mRNA population retains an intron in dendrites. Staufen2 interacts with this intron and enhances the distal dendritic localization of unspliced CaMKIIα mRNA. These findings suggest that intron retention could be a mechanism to modulate dendritic localization of synaptic mRNAs.


http://ift.tt/2trXkj9

Periadolescent Maturation of GABAergic Hyperpolarization at the Axon Initial Segment

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Gina Rinetti-Vargas, Khanhky Phamluong, Dorit Ron, Kevin J. Bender
Neuronal chloride levels are developmentally regulated. Early in life, high intracellular concentrations support chloride efflux and depolarization at GABAergic synapses. In mouse, intracellular chloride decreases over the first postnatal week in the somatodendritic compartment, eventually supporting mature, hyperpolarizing GABAergic inhibition. In contrast to this dendritic switch, it is less clear how GABAergic signaling at the axon initial segment (AIS) functions in mature pyramidal cells, as reports of both depolarization and hyperpolarization have been reported in the AIS past the first postnatal week. Here, we show that GABAergic signaling at the AIS of prefrontal pyramidal cells, indeed, switches polarity from depolarizing to hyperpolarizing but does so over a protracted periadolescent period. This is the most delayed maturation in chloride reversal in any structure studied to date and suggests that chandelier cells, which mediate axo-axonic inhibition, play a unique role in the periadolescent maturation of prefrontal circuits.

Graphical abstract

Teaser

Rinetti-Vargas et al. examine the development of chloride reversal potential (ECl), which determines GABAergic synapse polarity, in the axon initial segment of mouse prefrontal layer 2/3 pyramidal cells. They find that axon initial segment ECl hyperpolarizes over a periadolescent development period, eventually matching dendritic values.


http://ift.tt/2tsfIbA

The Ubiquitination of PINK1 Is Restricted to Its Mature 52-kDa Form

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Yuhui Liu, Cristina Guardia-Laguarta, Jiang Yin, Hediye Erdjument-Bromage, Brittany Martin, Michael James, Xuejun Jiang, Serge Przedborski
Along with Parkin, PINK1 plays a critical role in maintaining mitochondrial quality control. Although PINK1 is expressed constitutively, its level is kept low in healthy mitochondria by polyubiquitination and ensuing proteasomal degradation of its mature, 52 kDa, form. We show here that the target of PINK1 polyubiquitination is the mature form and is mediated by ubiquitination of a conserved lysine at position 137. Notably, the full-length protein also contains Lys-137 but is not ubiquitinated. On the basis of our data, we propose that cleavage of full-length PINK1 at Phe-104 disrupts the major hydrophobic membrane-spanning domain in the protein, inducing a conformation change in the resultant mature form that exposes Lys-137 to the cytosol for subsequent modification by the ubiquitination machinery. Thus, the balance between the full-length and mature PINK1 allows its levels to be regulated via ubiquitination of the mature form and ensures that PINK1 functions as a mitochondrial quality control factor.

Graphical abstract

Teaser

PINK1 mutations cause Parkinson's disease. PINK1 is cleaved into a shorter 52-kDa form at the mitochondrial membrane, but regulation of the turnover of cleaved PINK1 is unknown. Liu et al. show that polyubiquitination of cleaved PINK1 regulates its degradation via the proteasome.


http://ift.tt/2ts6UT0

Stromal Cell-Derived Factor 1 Mediates Immune Cell Attraction upon Urinary Tract Infection

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Batya Isaacson, Tehila Hadad, Ariella Glasner, Chamutal Gur, Zvi Granot, Gilad Bachrach, Ofer Mandelboim
Urinary tract infection (UTI) is the most common type of bacterial infection in humans. Fifty percent of all women will experience at least one UTI in their lifetime, with uropathogenic Escherichia coli (UPEC) accounting for 80% of reported cases. UTI evokes a complex, well-timed immune response that is crucial for bacterial clearance. The majority of immune cells participating in the immune response are absent from the healthy bladder, and the mechanisms used to recruit them upon UTI are not fully understood. Here, we show that immediately after UPEC infection, bladder epithelial cells secrete stromal cell-derived factor 1 (SDF-1), initiating immune cell accumulation at the site of infection. SDF-1 blockade significantly reduced immune cell migration to the infected bladder, resulting in severe exacerbation of infection. We also show that FimH, the adhesin of type 1 fimbria, one of UPEC's virulence factors, is directly involved in the secretion of SDF-1 upon UTI.

Graphical abstract

Teaser

Urinary tract infections (UTIs) are mainly caused by uropathogenic Escherichia coli (UPEC) and evoke a complex immune response. Isaacson et al. show that upon UPEC infection, bladder epithelial cells secrete the chemokine stromal cell-derived factor 1, triggering the migration and accumulation of immune cells at the site of infection.


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Identification of a Druggable Pathway Controlling Glioblastoma Invasiveness

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Nora Pencheva, Mark C. de Gooijer, Daniel J. Vis, Lodewyk F.A. Wessels, Tom Würdinger, Olaf van Tellingen, René Bernards
Diffuse and uncontrollable brain invasion is a hallmark of glioblastoma (GBM), but its mechanism is understood poorly. We developed a 3D ex vivo organotypic model to study GBM invasion. We demonstrate that invading GBM cells upregulate a network of extracellular matrix (ECM) components, including multiple collagens, whose expression correlates strongly with grade and clinical outcome. We identify interferon regulatory factor 3 (IRF3) as a transcriptional repressor of ECM factors and show that IRF3 acts as a suppressor of GBM invasion. Therapeutic activation of IRF3 by inhibiting casein kinase 2 (CK2)—a negative regulator of IRF3—downregulated the expression of ECM factors and suppressed GBM invasion in ex vivo and in vivo models across a panel of patient-derived GBM cell lines representative of the main molecular GBM subtypes. Our data provide mechanistic insight into the invasive capacity of GBM tumors and identify a potential therapy to inhibit GBM invasion.

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Teaser

Pencheva et al. describe an ex vivo organotypic brain slice model of glioblastoma invasiveness. Using this model, the authors discover a pro-invasive network of extracellular matrix collagens that are transcriptionally repressed by interferon regulatory factor 3. Small-molecule targeting of casein kinase 2 inhibits invasion by activating interferon regulatory factor 3.


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Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Kristen Therese Thomas, Bart Russell Anderson, Niraj Shah, Stephanie Elaine Zimmer, Daniel Hawkins, Arielle Nicole Valdez, Qiaochu Gu, Gary Jonathan Bassell
Genomic studies have repeatedly associated variants in the gene encoding the microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling. Inhibition of miR-137 ablates Nrg1α-induced increases in dendritic protein synthesis, phosphorylated S6, AMPA receptor subunits, and outgrowth. Inhibition of miR-137 also blocks mTORC1-dependent responses to BDNF, including increased mRNA translation and dendritic outgrowth, while leaving mTORC1-independent S6 phosphorylation intact. We conclude that miR-137 regulates neuronal responses to Nrg1α and BDNF through convergent mechanisms, which might contribute to schizophrenia risk by altering neural development.

Graphical abstract

Teaser

Thomas et al. show that the schizophrenia-associated microRNA miR-137 regulates neuronal responses to neuregulin-1α and BDNF signaling. miR-137 targets multiple components of the PI3K-Akt-mTOR pathway, which act downstream of both neuregulin and BDNF. Inhibition of miR-137 blocks stimulus-induced dendritic protein synthesis and outgrowth among other responses critical to neuronal development.


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DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Adone Mohd-Sarip, Miriam Teeuwssen, Alice G. Bot, Maria J. De Herdt, Stefan M. Willems, Robert J. Baatenburg de Jong, Leendert H.J. Looijenga, Diana Zatreanu, Karel Bezstarosti, Job van Riet, Edwin Oole, Wilfred F.J. van Ijcken, Harmen J.G. van de Werken, Jeroen A. Demmers, Riccardo Fodde, C. Peter Verrijzer
The Nucleosome Remodeling and Deacetylase (NURD) complex is a key regulator of cell differentiation that has also been implicated in tumorigenesis. Loss of the NURD subunit Deleted in Oral Cancer 1 (DOC1) is associated with human oral squamous cell carcinomas (OSCCs). Here, we show that restoration of DOC1 expression in OSCC cells leads to a reversal of epithelial-mesenchymal transition (EMT). This is caused by the DOC1-dependent targeting of NURD to repress key transcriptional regulators of EMT. NURD recruitment drives extensive epigenetic reprogramming, including eviction of the SWI/SNF remodeler, formation of inaccessible chromatin, H3K27 deacetylation, and binding of PRC2 and KDM1A, followed by H3K27 methylation and H3K4 demethylation. Strikingly, depletion of SWI/SNF mimics the effects of DOC1 re-expression. Our results suggest that SWI/SNF and NURD function antagonistically to control chromatin state and transcription. We propose that disturbance of this dynamic equilibrium may lead to defects in gene expression that promote oncogenesis.

Graphical abstract

Teaser

Mohd-Sarip et al. find that DOC1-dependent recruitment of NURD leads to reversal of the epithelial-mesenchymal transition (EMT) in oral cancer cells. Promoter binding of NURD drives SWI/SNF eviction, formation of repressive chromatin, and transcriptional repression of master regulators of EMT. The authors propose that remodeler antagonism controls reprogramming of EMT at the chromatin level.


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Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Laura T. Haas, Santiago V. Salazar, Levi M. Smith, Helen R. Zhao, Timothy O. Cox, Charlotte S. Herber, Andrew P. Degnan, Anand Balakrishnan, John E. Macor, Charles F. Albright, Stephen M. Strittmatter
Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrP^C) bound to Aβo. The SAM compound prevents Aβo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5's role in Aβo-dependent AD phenotypes is separate from its role in glutamate signaling and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window.

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Teaser

Haas et al. investigate the role of mGluR5 in Alzheimer's disease. They describe a compound that blocks the action of amyloid β through this receptor but preserves glutamate signaling. This amyloid-selective blocker rescues transgenic mouse models of Alzheimer's disease and, by sparing glutamate signaling, avoids the side effects of typical mGluR5 antagonists.


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Time-Resolved Fast Mammalian Behavior Reveals the Complexity of Protective Pain Responses

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Liam E. Browne, Alban Latremoliere, Brendan P. Lehnert, Alyssa Grantham, Catherine Ward, Chloe Alexandre, Michael Costigan, Frédéric Michoud, David P. Roberson, David D. Ginty, Clifford J. Woolf
Potentially harmful stimuli are detected at the skin by nociceptor sensory neurons that drive rapid protective withdrawal reflexes and pain. We set out to define, at a millisecond timescale, the relationship between the activity of these sensory neurons and the resultant behavioral output. Brief optogenetic activation of cutaneous nociceptors was found to activate only a single action potential in each fiber. This minimal input was used to determine high-speed behavioral responses in freely behaving mice. The localized stimulus generated widespread dynamic repositioning and alerting sub-second behaviors whose nature and timing depended on the context of the animal and its position, activity, and alertness. Our findings show that the primary response to injurious stimuli is not limited, fixed, or localized, but is dynamic, and that it involves recruitment and gating of multiple circuits distributed throughout the central nervous system at a sub-second timescale to effectively both alert to the presence of danger and minimize risk of harm.

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Teaser

Browne et al. find that the responses evoked by noxious stimuli, when examined at a millisecond resolution, are not fixed, localized, or limited to reflex withdrawal but are instead coordinated globally across the body in a sub-second time frame to alert the animal and limit potential harm.


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Exosomes Mediate Mobilization of Autocrine Wnt10b to Promote Axonal Regeneration in the Injured CNS

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Nardos G. Tassew, Jason Charish, Alireza P. Shabanzadeh, Valbona Luga, Hidekiyo Harada, Nahal Farhani, Philippe D'Onofrio, Brian Choi, Ahmad Ellabban, Philip E.B. Nickerson, Valerie A. Wallace, Paulo D. Koeberle, Jeffrey L. Wrana, Philippe P. Monnier
Developing strategies that promote axonal regeneration within the injured CNS is a major therapeutic challenge, as axonal outgrowth is potently inhibited by myelin and the glial scar. Although regeneration can be achieved using the genetic deletion of PTEN, a negative regulator of the mTOR pathway, this requires inactivation prior to nerve injury, thus precluding therapeutic application. Here, we show that, remarkably, fibroblast-derived exosomes (FD exosomes) enable neurite growth on CNS inhibitory proteins. Moreover, we demonstrate that, upon treatment with FD exosomes, Wnt10b is recruited toward lipid rafts and activates mTOR via GSK3β and TSC2. Application of FD exosomes shortly after optic nerve injury promoted robust axonal regeneration, which was strongly reduced in Wnt10b-deleted animals. This work uncovers an intercellular signaling pathway whereby FD exosomes mobilize an autocrine Wnt10b-mTOR pathway, thereby awakening the intrinsic capacity of neurons for regeneration, an important step toward healing the injured CNS.

Graphical abstract

Teaser

Tassew et al. find that FD exosomes induce relocalization of Wnt10b into lipid rafts, thereby activating mTOR and promoting axonal growth in an inhibitory environment. These exosomes also promote axonal regeneration following optic nerve injury. Thus, they represent a powerful tool to stimulate axonal regrowth in the injured CNS.


http://ift.tt/2trXjM7

Somatostatin Neurons in the Basal Forebrain Promote High-Calorie Food Intake

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Chen Zhu, Yun Yao, Yan Xiong, Mingxiu Cheng, Jing Chen, Rui Zhao, Fangzhou Liao, Runsheng Shi, Sen Song
Obesity has become a global issue, and the overconsumption of food is thought to be a major contributor. However, the regulatory neural circuits that regulate palatable food consumption remain unclear. Here, we report that somatostatin (SOM) neurons and GABAergic (VGAT) neurons in the basal forebrain (BF) play specific roles in regulating feeding. Optogenetic stimulation of BF SOM neurons increased fat and sucrose intake within minutes and promoted anxiety-like behaviors. Furthermore, optogenetic stimulation of projections from BF SOM neurons to the lateral hypothalamic area (LHA) selectively resulted in fat intake. In addition, activation of BF VGAT neurons rapidly induced general food intake and gnawing behaviors. Whole-brain mapping of inputs and outputs showed that BF SOM neurons form bidirectional connections with several brain areas important in feeding and regulation of emotion. Collectively, these results suggest that BF SOM neurons play a selective role in hedonic feeding.

Graphical abstract

Teaser

Zhu et al. uncover a crucial neuronal population in the mouse basal forebrain (BF) that induces hedonic feeding. Activation of BF somatostatin neurons specifically leads to high-calorie food intake and induces anxiety-like behaviors. This may be related to stress-induced overeating of palatable food, which contributes to obesity problems.


http://ift.tt/2tsdV6u

RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Yong-Hyun Han, Hyeon-Ji Kim, Hyelin Na, Min-Woo Nam, Ju-Yeon Kim, Jun-Seok Kim, Seung-Hoi Koo, Mi-Ock Lee
The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH.

Graphical abstract

Teaser

Han et al. find that RORα is a key regulator of M1/M2 polarization in liver macrophages. Myeloid-specific knockout of RORα display decreased M2/M1 ratio in Kupffer cells and enhanced susceptibility to nonalcoholic steatohepatitis. This function of RORα may suggest therapeutic strategies for nonalcoholic steatohepatitis.


http://ift.tt/2trYCul

Microbial-Host Co-metabolites Are Prodromal Markers Predicting Phenotypic Heterogeneity in Behavior, Obesity, and Impaired Glucose Tolerance

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Marc-Emmanuel Dumas, Alice R. Rothwell, Lesley Hoyles, Thomas Aranias, Julien Chilloux, Sophie Calderari, Elisa M. Noll, Noémie Péan, Claire L. Boulangé, Christine Blancher, Richard H. Barton, Quan Gu, Jane F. Fearnside, Chloé Deshayes, Christophe Hue, James Scott, Jeremy K. Nicholson, Dominique Gauguier
The influence of the gut microbiome on metabolic and behavioral traits is widely accepted, though the microbiome-derived metabolites involved remain unclear. We carried out untargeted urine ¹H-NMR spectroscopy-based metabolic phenotyping in an isogenic C57BL/6J mouse population (n = 50) and show that microbial-host co-metabolites are prodromal (i.e., early) markers predicting future divergence in metabolic (obesity and glucose homeostasis) and behavioral (anxiety and activity) outcomes with 94%–100% accuracy. Some of these metabolites also modulate disease phenotypes, best illustrated by trimethylamine-N-oxide (TMAO), a product of microbial-host co-metabolism predicting future obesity, impaired glucose tolerance (IGT), and behavior while reducing endoplasmic reticulum stress and lipogenesis in 3T3-L1 adipocytes. Chronic in vivo TMAO treatment limits IGT in HFD-fed mice and isolated pancreatic islets by increasing insulin secretion. We highlight the prodromal potential of microbial metabolites to predict disease outcomes and their potential in shaping mammalian phenotypic heterogeneity.

Graphical abstract

Teaser

Dumas et al. study the metabolic and behavioral phenotypic heterogeneity induced by a high-fat diet intervention in an isogenic mouse population model. Using ¹H-NMR spectroscopy, they identify pre-interventional urinary metabolic signatures (including microbial-host co-metabolites) predicting future phenotypic heterogeneity. In particular, TMAO corrects endoplasmic reticulum stress and glucose tolerance.


http://ift.tt/2trNmOH

The Complete Structure of the Mycobacterium smegmatis 70S Ribosome

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Jendrik Hentschel, Chloe Burnside, Ingrid Mignot, Marc Leibundgut, Daniel Boehringer, Nenad Ban
The ribosome carries out the synthesis of proteins in every living cell. It consequently represents a frontline target in anti-microbial therapy. Tuberculosis ranks among the leading causes of death worldwide, due in large part to the combination of difficult-to-treat latency and antibiotic resistance. Here, we present the 3.3-Å cryo-EM structure of the 70S ribosome of Mycobacterium smegmatis, a close relative to the human pathogen Mycobacterium tuberculosis. The structure reveals two additional ribosomal proteins and localizes them to the vicinity of drug-target sites in both the catalytic center and the decoding site of the ribosome. Furthermore, we visualized actinobacterium-specific rRNA and protein expansions that extensively remodel the ribosomal surface with implications for polysome organization. Our results provide a foundation for understanding the idiosyncrasies of mycobacterial translation and reveal atomic details of the structure that will facilitate the design of anti-tubercular therapeutics.

Graphical abstract

Teaser

The M. tuberculosis ribosome is an important target for antibiotics in anti-tubercular therapy. Hentschel et al. determine the high-resolution structure of the related Mycobacterium smegmatis ribosome and provide a structural framework for antibiotic development and for the understanding of species-specific peculiarities of translation in Actinobacteria.


http://ift.tt/2trRQVD

Post-termination Ribosome Intermediate Acts as the Gateway to Ribosome Recycling

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Arjun Prabhakar, Mark C. Capece, Alexey Petrov, Junhong Choi, Joseph D. Puglisi
During termination of translation, the nascent peptide is first released from the ribosome, which must be subsequently disassembled into subunits in a process known as ribosome recycling. In bacteria, termination and recycling are mediated by the translation factors RF, RRF, EF-G, and IF3, but their precise roles have remained unclear. Here, we use single-molecule fluorescence to track the conformation and composition of the ribosome in real time during termination and recycling. Our results show that peptide release by RF induces a rotated ribosomal conformation. RRF binds to this rotated intermediate to form the substrate for EF-G that, in turn, catalyzes GTP-dependent subunit disassembly. After the 50S subunit departs, IF3 releases the deacylated tRNA from the 30S subunit, thus preventing reassembly of the 70S ribosome. Our findings reveal the post-termination rotated state as the crucial intermediate in the transition from termination to recycling.

Graphical abstract

Teaser

Ribosome intersubunit conformation plays a critical role in ribosome recycling after translation termination. Prabhakar et al. use single-molecule techniques to temporally resolve the post-termination intersubunit rotation that promotes factor-mediated disassembly of the ribosome. The observed ribosome conformational dynamics clarified the roles of the protein factors and timing of recycling events.


http://ift.tt/2trTtSW

Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Katherine S. Bridge, Kunal M. Shah, Yigen Li, Daniel E. Foxler, Sybil C.K. Wong, Duncan C. Miller, Kathryn M. Davidson, John G. Foster, Ruth Rose, Michael R. Hodgkinson, Paulo S. Ribeiro, A. Aziz Aboobaker, Kenta Yashiro, Xiaozhong Wang, Paul R. Graves, Michael J. Plevin, Dimitris Lagos, Tyson V. Sharp
As core components of the microRNA-induced silencing complex (miRISC), Argonaute (AGO) proteins interact with TNRC6 proteins, recruiting other effectors of translational repression/mRNA destabilization. Here, we show that LIMD1 coordinates the assembly of an AGO-TNRC6 containing miRISC complex by binding both proteins simultaneously at distinct interfaces. Phosphorylation of AGO2 at Ser 387 by Akt3 induces LIMD1 binding, which in turn enables AGO2 to interact with TNRC6A and downstream effector DDX6. Conservation of this serine in AGO1 and 4 indicates this mechanism may be a fundamental requirement for AGO function and miRISC assembly. Upon CRISPR-Cas9-mediated knockout of LIMD1, AGO2 miRNA-silencing function is lost and miRNA silencing becomes dependent on a complex formed by AGO3 and the LIMD1 family member WTIP. The switch to AGO3 utilization occurs due to the presence of a glutamic acid residue (E390) on the interaction interface, which allows AGO3 to bind to LIMD1, AJUBA, and WTIP irrespective of Akt signaling.

Graphical abstract

Teaser

Argonaute (AGO) proteins mediate post-transcriptional gene silencing through formation of the microRNA-induced silencing complex (miRISC). Bridge et al. identify LIM-domain-containing proteins as essential for miRISC formation through a phosphorylation-dependent mechanism. This is critical for post-transcriptional gene silencing and reveals that miRISC functionality is maintained by "AGO switching."


http://ift.tt/2trPbuY

An Ancient Pseudoknot in TNF-α Pre-mRNA Activates PKR, Inducing eIF2α Phosphorylation that Potently Enhances Splicing

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Lise Sarah Namer, Farhat Osman, Yona Banai, Benoît Masquida, Rodrigo Jung, Raymond Kaempfer
Tumor necrosis factor alpha (TNF-α) is expressed promptly during inflammatory responses. Efficient TNF-α mRNA splicing is achieved through a 3′ UTR element that activates RNA-dependent eIF2α protein kinase (PKR). The TNF-α RNA activator, we show, folds into a pseudoknot conserved from teleost fish to humans, critical for PKR activation and mRNA splicing. The pseudoknot constrains the RNA into two double-helical stacks having parallel axes, permitting facile PKR dimerization and trans-autophosphorylation needed for kinase activation. Mutations show that the PKR activator potently enhances splicing without inhibiting translation. eIF2α phosphorylation represses translation and is essential for coping with cellular stress, yet PKR-enabled TNF mRNA splicing depends strictly on eIF2α phosphorylation. Indeed, eIF2α phosphorylation at Serine51 is necessary and sufficient to achieve highly efficient splicing, extending its role from negative control of translation to positive control of splicing. This mechanism, operational in human peripheral blood mononuclear cells (PBMCs), links stress signaling to protective immunity through TNF mRNA splicing rendered efficient upon eIF2α phosphorylation.

Graphical abstract

Teaser

Tumor necrosis factor (TNF) is expressed promptly during inflammatory responses. Namer et al. define the structure and function of a TNF RNA element that promotes mRNA splicing. It enables splicing by inducing phosphorylation of eIF2α by the RNA-activated enzyme PKR, a cellular stress response previously thought only to block translation.


http://ift.tt/2trQDO7

Entosis Is Induced by Glucose Starvation

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Jens C. Hamann, Alexandra Surcel, Ruoyao Chen, Carolyn Teragawa, John G. Albeck, Douglas N. Robinson, Michael Overholtzer
Entosis is a mechanism of cell death that involves neighbor cell ingestion. This process occurs in cancers and promotes a form of cell competition, where winner cells engulf and kill losers. Entosis is driven by a mechanical differential that allows softer cells to eliminate stiffer cells. While this process can be induced by matrix detachment, whether other stressors can activate entosis is unknown. Here, we find that entosis is induced in adherent cells by glucose withdrawal. Glucose withdrawal leads to a bimodal distribution of cells based on their deformability, where stiffer cells appear in a manner requiring the energy-sensing AMP-activated protein kinase (AMPK). We show that loser cells with high levels of AMPK activity are eliminated by winners through entosis, which supports winner cell proliferation under nutrient-deprived conditions. Our findings demonstrate that entosis serves as a cellular response to metabolic stress that enables nutrient recovery through neighbor cell ingestion.

Graphical abstract

Teaser

Entosis has been shown to occur in human cancers and promotes cell competition. Hamann et al. now show that nutrient deprivation, in the form of glucose withdrawal, induces entosis to support the outgrowth of winner cells that feed off of losers.


http://ift.tt/2trKem4

Laminin Levels Regulate Tissue Migration and Anterior-Posterior Polarity during Egg Morphogenesis in Drosophila

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): María C. Díaz de la Loza, Alfonsa Díaz-Torres, Federico Zurita, Alicia E. Rosales-Nieves, Emad Moeendarbary, Kristian Franze, María D. Martín-Bermudo, Acaimo González-Reyes
Basement membranes (BMs) are specialized extracellular matrices required for tissue organization and organ formation. We study the role of laminin and its integrin receptor in the regulation of tissue migration during Drosophila oogenesis. Egg production in Drosophila involves the collective migration of follicle cells (FCs) over the BM to shape the mature egg. We show that laminin content in the BM increases with time, whereas integrin amounts in FCs do not vary significantly. Manipulation of integrin and laminin levels reveals that a dynamic balance of integrin-laminin amounts determines the onset and speed of FC migration. Thus, the interplay of ligand-receptor levels regulates tissue migration in vivo. Laminin depletion also affects the ultrastructure and biophysical properties of the BM and results in anterior-posterior misorientation of developing follicles. Laminin emerges as a key player in the regulation of collective cell migration, tissue stiffness, and the organization of anterior-posterior polarity in Drosophila.

Graphical abstract

Teaser

Collective cell migration requires cell-ECM interactions. Using the fruit fly ovary, Díaz de la Loza et al. find that the ECM component laminin controls the onset and speed of epithelial sheet migration. Because laminin depletion also results in aberrant anterior-posterior polarity, laminin regulates coordinated migration during organogenesis and maintains axial polarity.


http://ift.tt/2ts9LeD

Positive Regulation of Interleukin-1β Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation

Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Xue Zhang, Peng Liu, Christie Zhang, Direkrit Chiewchengchol, Fan Zhao, Hongbo Yu, Jingyu Li, Hiroto Kambara, Kate Y. Luo, Arvind Venkataraman, Ziling Zhou, Weidong Zhou, Haiyan Zhu, Li Zhao, Jiro Sakai, Yuanyuan Chen, Ye-Shih Ho, Besnik Bajrami, Bing Xu, Leslie E. Silberstein, Tao Cheng, Yuanfu Xu, Yuehai Ke, Hongbo R. Luo
Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of extracellular components via S-glutathionylation is unknown. Using a screening approach, we identified ROS-mediated cysteine S-glutathionylation on several extracellular cytokines. Glutathionylation of the highly conserved Cys-188 in IL-1β positively regulates its bioactivity by preventing its ROS-induced irreversible oxidation, including sulfinic acid and sulfonic acid formation. We show this mechanism protects IL-1β from deactivation by ROS in an in vivo system of irradiation-induced bone marrow (BM) injury. Glutaredoxin 1 (Grx1), an enzyme that catalyzes deglutathionylation, was present and active in the extracellular space in serum and the BM, physiologically regulating IL-1β glutathionylation and bioactivity. Collectively, we identify cysteine S-glutathionylation as a cytokine regulatory mechanism that could be a therapeutic target in the treatment of various infectious and inflammatory diseases.

Graphical abstract

Teaser

Zhang et al. reveal that cysteine S-glutathionylation of the highly conserved Cys-188 residue of IL-1β positively regulates its bioactivity by preventing its irreversible ROS-elicited deactivation. ROS-induced cysteine glutathionylation and its modulation by Glutaredoxin 1 (Grx1) are key physiological regulatory mechanisms controlling IL-1β activity, providing a potential therapeutic target in the treatment of infectious and inflammatory diseases.


http://ift.tt/2tsceWk

A Molecular and Preclinical Comparison of the PD-1 targeted T cell Checkpoint Inhibitors Nivolumab and Pembrolizumab

Publication date: Available online 4 July 2017
Source:Seminars in Oncology
Author(s): Petros Fessas, Hassal Lee, Shinji Ikemizu, Tobias Janowitz
T cell checkpoint inhibition has a profound impact on cancer care and the two Programmed cell death protein 1 (PD-1) targeted antibodies nivolumab and pembrolizumab have been leading this therapeutic revolution. Their clinical comparability is a highly relevant topic of discussion, but to a significant degree is a consequence of their molecular properties. Here we provide a molecular, preclinical, and early clinical comparison of the two antibodies, based on the available data and recent literature. We acknowledge the limitations of such comparisons, but suggest that based on the available data, differences in clinical trial outcomes between nivolumab and pembrolizumab are more likely drug-independent than drug-dependent.



http://ift.tt/2usA6tp

Co-delivery of a growth factor and a tissue-protective molecule using elastin biopolymers accelerates wound healing in diabetic mice

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Julie Devalliere, Kevin Dooley, Yong Yu, Sarah S. Kelangi, Basak E. Uygun, Martin L. Yarmush
Growth factor therapy is a promising approach for chronic diabetic wounds, but strategies to efficiently and cost-effectively deliver active molecules to the highly proteolytic wound environment remain as major obstacles. Here, we re-engineered keratinocyte growth factor (KGF) and the cellular protective peptide ARA290 into a protein polymer suspension with the purpose of increasing their proteolytic resistance, thus their activity in vivo. KGF and ARA290 were fused with elastin-like peptide (ELP), a protein polymer derived from tropoelastin, that confers the ability to separate into a colloidal suspension of liquid-like coacervates. ELP fusion did not diminish peptides activities as demonstrated by ability of KGF-ELP to accelerate keratinocyte proliferation and migration, and ARA290-ELP to protect cells from apoptosis. We examined the healing effect of ARA290-ELP and KGF-ELP alone or in combination, in a full-thickness diabetic wound model. In this model, ARA290-ELP was found to accelerate healing, notably by increasing angiogenesis in the wound bed. We further showed that co-delivery of ARA290 and KGF, with the 1:4 KGF-ELP to ARA290-ELP ratio, was the most effective wound treatment with the fastest healing rate, the thicker granulation tissue and regenerated epidermis after 28 days. Overall, this study shows that ARA290-ELP and KGF-ELP constitute promising new therapeutics for treatment of chronic wounds.



http://ift.tt/2tOgd1S

Enhanced osteogenic activity of poly(ester urea) scaffolds using facile post-3D printing peptide functionalization strategies

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Shan Li, Yanyi Xu, Jiayi Yu, Matthew L. Becker
Additive manufacturing has the potential to revolutionize regenerative medicine, but the harsh thermal or photochemical conditions during the 3D printing process limit the inclusion of drugs, growth factors and other biologics within the resulting scaffolds. Functionalization strategies that enable specific placement of bioactive species on the surface of 3D printed structures following the printing process afford a promising approach to sidestep the harsh conditions and incorporate these valuable bioactive molecules with precise control over concentration. Herein, resorbable polymer scaffolds were prepared from propargyl functionalized L-phenylalanine-based poly(ester urea)s (PEUs). Osteogenic growth peptide (OGP) or bone morphogenic protein-2 (BMP-2) peptides were immobilized on PEU scaffolds through surface available propargyl groups via copper-catalyzed azide alkyne cycloaddition (CuAAC) post 3D printing. The presence of either OGP or BMP-2 significantly enhanced hMSCs osteogenic differentiation compared to unfunctionalized scaffolds.



http://ift.tt/2uMjY5e

A strategy for actualization of active targeting nanomedicine practically functioning in a living body

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Kyoung Jin Lee, Seol Hwa Shin, Jae Hee Lee, Eun Jin Ju, Yun-Yong Park, Jung Jin Hwang, Young-Ah Suh, Seung-Mo Hong, Se Jin Jang, Jung Shin Lee, Si Yeol Song, Seong-Yun Jeong, Eun Kyung Choi
Designing nanocarriers with active targeting has been increasingly emphasized as for an ideal delivery mechanism of anti-cancer therapeutic agents, but the actualization has been constrained by lack of reliable strategy ultimately applicable. Here, we designed and verified a strategy to achieve active targeting nanomedicine that works in a living body, utilizing animal models bearing a patient's tumor tissue and subjected to the same treatments that would be used in the clinic. The concept for this strategy was that a novel peptide probe and its counterpart protein, which responded to a therapy, were identified, and then the inherent ability of the peptide to target the designated tumor protein was used for active targeting in vivo. An initial dose of ionizing radiation was locally delivered to the gastric cancer (GC) tumor of a patient-derived xenograft mouse model, and phage-displayed peptide library was intravenously injected. The peptides tightly bound to the tumor were recovered, and the counterpart protein was subsequently identified. Peptide-conjugated liposomal drug showed dramatically improved therapeutic efficacy and possibility of diagnostic imaging with radiation. These results strongly suggested the potential of our strategy to achieve in vivo functional active targeting and to be applied clinically for human cancer treatment.



http://ift.tt/2urgQMB

Riboflavin-containing telodendrimer nanocarriers for efficient doxorubicin delivery: High loading capacity, increased stability, and improved anticancer efficacy

Publication date: October 2017
Source:Biomaterials, Volume 141
Author(s): Dandan Guo, Changying Shi, Xu Wang, Lili Wang, Shengle Zhang, Juntao Luo
We have developed two linear-dendritic telodendrimers (TDs) with rational design using amphiphilic riboflavin (Rf) as building blocks for efficient doxorubicin (DOX) delivery. Micellar TD nanoparticles (NPs) are composed of a hydrophilic polyethylene glycol (PEG) shell and a Rf-containing affinitive core for DOX encapsulation. Strong DOX-Rf interactions and amphiphilic Rf structure render these nanocarriers with an ultra-high DOX loading capacity (>1/1, DOX/TD, w/w), ∼100% loading efficiency, the sustained drug release and the optimal particle sizes (20–40 nm) for efficient tumor-targeted drug delivery. These nanoformulations significantly prolonged DOX circulation time in the blood without the accelerated clearance observed after multiple injections. DOX-TDs target several types of tumors efficiently in vivo, e.g. Raji lymphoma, MDA-MB-231 breast cancer, and SKOV-3 ovarian cancer. In vivo maximum tolerated dose (MTD) of DOX was increased by 2–2.5 folds for the nanoformulations in mice relative to those of free DOX and Doxil^®. These nanoformulations significantly inhibited tumor growth and prolonged survival of mice bearing SKOV-3 ovarian cancer xenografts. In summary, Rf-containing nanoformulations with high DOX loading capacity, improved stability and efficient tumor targeting lead to superior antitumor efficacy, which merit the further development for clinical application.



http://ift.tt/2tOEFjD

HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles

Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Regina Medvedev, Daniela Ploen, Catrina Spengler, Fabian Elgner, Huimei Ren, Sarah Bunten, Eberhard Hildt
Viruses are known to exploit the autophagic machinery for their own benefit. In case of the hepatitis C virus autophagy is induced. As autophagy serves as a degradation pathway to maintain cellular homeostasis, it is activated in response to cellular stress such as elevated levels of reactive oxygen species (ROS). Elevated levels of ROS trigger phosphorylation of the autophagic adaptor protein p62 on Ser349 (pS[349] p62) that is involved in the induction of autophagy. Consequently, pS[349] p62 binds with a higher affinity to Keap1 thereby releasing Nrf2 from the complex with Keap1. Although the released Nrf2 should induce as a heterodimer with the sMaf proteins the expression of Nrf2/ARE-dependent genes, in HCV-positive cells no activation of cytoprotective genes occurs even though elevated amounts of pS[349] p62 are present. In HCV-positive cells, free Nrf2 is trapped via delocalized sMaf proteins at the replicon complexes on the cytoplasmic face of the ER and is therefore prevented from its entry into the nucleus. Scavenging of ROS leads to decreased levels of pS[349] p62 and impaired induction of autophagy. Both, inhibition of autophagy and scavenging of ROS result in decreased amounts of released viral particles. Taken together, these data identify an intricate mechanism of HCV-dependent inhibition of Nrf2/ARE-mediated gene expression which counteracts pS[349] p62-induced activation of Nrf2. Thereby elevated ROS-levels are preserved that in turn activate autophagy to favor HCV particle release.

Graphical abstract

http://ift.tt/2trYjQf

Aesthetic outcomes of liposuction after breast reconstruction using exclusive fat grafting

Sir

http://ift.tt/2sIhW9z

The cubital tunnel syndrome caused by the intraneural or extraneural ganglion cysts-cases report and review of the literature

Cubital tunnel syndrome is the second most common nerve compression syndrome in peripheral nerve compression disease. Although potential ulnar nerve entrapment can occur multiple points along its course, such as the arcade of struthers, the medial intermuscular septum, the medial epicondyle, the cubital tunnel and the deep flexor pronator aponeurosis. The most common site of entrapment is the cubital tunnel. However, cubital tunnel syndrome could also be caused by the occupying masses along the course of ulnar nerve, such as intraneural or extraneural ganglia.

http://ift.tt/2trCzE1

Greenlandic water and sanitation systems—identifying system constellation and challenges

Abstract

A good water supply and wastewater management is essential for a local sustainable community development. This is emphasized in the new global goals of the UN Sustainable Development, where the sixth objective is to: "Ensure availability and sustainable management of water and sanitation for all" (United Nations 2015). This obviously raises the question of how this can be achieved considering the very different conditions and cultures around the globe. This article presents the Greenlandic context and elucidates the current Greenland water supply system and wastewater management system from a socio-technical approach, focusing on the geographic, climatic and cultural challenges. The article identifies a diverse set of system constellations in different parts of Greenland and concludes with a discussion of health and quality of life implications.

http://ift.tt/2sOgk9m

Roots alterations in presence of phenanthrene may limit co-remediation implementation with Noccaea caerulescens

Abstract

Co-phytoremediation of both trace elements and polycyclic aromatic hydrocarbons (PAH) is an emerging technique to treat multi-contaminated soils. In this study, root morphological and structural features of the heavy metal hyperaccumulator Noccaea caerulescens, exposed to a model PAH phenanthrene (PHE) in combination with cadmium (Cd), were observed. In vitro cultivated seedlings were exposed to 2 mM of PHE and/or 5 μM of Cd for 1 week. Co-phytoremediation effectiveness appeared restricted because of a serious inhibition (about 40%) of root and shoot biomass production in presence of PHE, while Cd had no significant adverse effect on these parameters. The most striking effects of PHE on roots were a decreased average root diameter, the inhibition of cell and root hair elongation and the promotion of lateral root formation. Moreover, endodermal cells with suberin lamellae appeared closer to the root apex when exposed to PHE compared to control and Cd treatments, possibly due to modified lateral root formation. The stage with well-developed suberin lamellae was not influenced by PHE whereas peri-endodermal layer development was impaired in PHE-treated plants. Many of these symptoms were similar to a water-deficit response. These morphological and structural root modifications in response to PHE exposition might in turn limit Cd phytoextraction by N. caerulescens in co-contaminated soils.

http://ift.tt/2tjaXCK

First investigation of trace metal distribution in surface seawater and copepods of the south coast of Sfax (Tunisia)

Abstract

The increased metal loading from anthropogenic sources has affected aquatic ecosystems and has cascaded through food webs worldwide. Therefore, the evaluation of ecological impacts of anthropogenic metal has become increasingly important. In this paper, we monitored the concentration of six trace metals (Cd, Cu, Fe, Ni, Pb, and Zn) in the three copepod groups (cyclopoida, calanoida, and harpacticoida) and in seawater samples collected from the south coast of Sfax (Tunisia). Results showed that the concentration of Fe and Zn for all copepod groups was higher than that for other metals and that of Cd was the lowest in all groups. The mean increase in bioconcentration factor of metals in copepods ranged from 0.05 to 18.93 and followed the sequence Zn (18.93) > Fe (14.34) > Pb (6.41) > Cd (1.53) > Cu (0.10) > Ni (0.05). The copepods in the south coast of Sfax were found to have a great capacity to accumulate trace metals and act as contamination indicators. Comparative studies with those from the Luza zone indicate considerable bioaccumulation of trace metals (Pb and Ni) in all copepod groups namely in cyclopoida.

http://ift.tt/2sOBVih

Aquatic ecotoxicity of ashes from Brazilian savanna wildfires

Abstract

In a global scenario of climate change, several studies have predicted an increase in fires in different parts of the world. With the occurrence of rains following the fires in the Brazilian savanna (Cerrado biome), the compounds present in ashes may enter aquatic environments and cause adverse effects to these ecosystems. In this context, this study evaluated the potential toxicity of ashes from two areas of Cerrado and an area of pasture, through ecotoxicological bioassays and using three aquatic species from distinct trophic levels, which were exposed to different dilutions of ashes: the microcrustacean Ceriodaphnia dubia, the fish Danio rerio and the mollusc Biomphalaria glabrata. The ashes from the three sampled areas showed higher concentrations of some elements in relation to the soil samples (B, Ca, K, Mg, Mn, P, S, Si, Sr, Zn), but only a small quantity of these compounds was solubilised. Our data showed that all ash samples caused acute toxicity to C. dubia (48hs-LC₅₀ = 13.4 g L⁻¹; 48hs-LC₅₀ = 6.33 g L⁻¹; 48hs-LC₅₀ = 9.73 g L⁻¹ respectively for transition area, pasture, typical cerrado areas), while in relation to D. rerio and B. glabrata, no acute toxicity was observed when they were exposed to ashes from native Cerrado vegetation and pasture areas. Ashes from a transition area showed toxicity for D. rerio (48hs-LC₅₀ = 25.0 g L⁻¹); possibly, this was due to the combination of multiple preponderant inorganic elements of ashes with other organic compounds not analysed, such as polycyclic aromatic hydrocarbons (PAHs). In summary, these results suggest that wildfires may pose risks to zooplankton communities and emphasize the need for more studies to better understand the complexity of the ecological effects of fire on aquatic ecosystems.

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In vitro simulation of realistic gastric pressure profiles

Publication date: 30 September 2017
Source:European Journal of Pharmaceutical Sciences, Volume 107
Author(s): Felix Schneider, Regine Beeck, Melanie Hoppe, Mirko Koziolek, Werner Weitschies
Novel in vitro dissolution tools can aid the development of orally administered drugs by explaining dosage form related in vivo phenomena that are not explainable with standard test apparatuses. Such novel tools are able to mimic various parameters in accordance with gastrointestinal conditions. Hereby, in vivo occurring pressure events were shown to be of major importance since they largely affect dosage form disintegration, drug dissolution and subsequently resulting drug plasma concentration profiles. The aim of the present study was to investigate the feasibility of producing biorelevant pressure events with standard test apparatuses and with the dynamic open flow through test apparatus. For this purpose, we used the SmartPill®, a swallowable capsule that houses a pressure sensor and that was already applied to gather human in vivo data. Among the standard apparatuses, highest pressures were measured in the reciprocating cylinder apparatus and the disintegration tester. No relevant pressure peaks could be detected in the paddle apparatus and the mini paddle apparatus. In contrast, the dynamic open flow through test apparatus enabled the simulation of complete gastric pressure profiles as they occur in vivo. The present work underlines the potential of novel in vitro dissolution models as useful tools during the drug development process as well as for explanatory purposes.

Graphical abstract

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Zero order controlled release delivery of cholecalciferol from injectable biodegradable microsphere: In-vitro characterization and in-vivo pharmacokinetic studies

Publication date: 30 September 2017
Source:European Journal of Pharmaceutical Sciences, Volume 107
Author(s): Lalit Vora, Sita V G, Pradeep Vavia
Poly(lactic-co-glycolic acid) microspheres loaded with cholecalciferol (CL), more bioactive form of vitamin D was developed as an injectable controlled drug release system and was evaluated for its feasibility of once a month delivery. The CL loaded microspheres (CL-MS) were prepared by simple oil in water (O/W) emulsion–solvent evaporation technique incorporated with a stabilizer, Tocopherol Succinate (TS). Different formulation as well as process parameters were investigated namely concentration of emulsifier, concentration of stabilizer and drug: polymer mass ratios. The prepared CL-MS were evaluated for particle size, drug loading, in-vitro drug release and in-vivo pharmacokinetics in rats. The optimized formulation was found to have a mean particle size of 28.62±0.26μm, Encapsulation Efficiency (EE) of 94.4±5.4% and drug loading of 5.19±0.29% with CL:TS ratio of 2:1. It was found that the EE drastically decreased (26±5.9%) in the absence of stabilizer (TS) indicating its role in stabilization of CL during formulation. DSC and XRD studies indicated that CL existed in an amorphous structure in the polymer matrix. SEM of the CL-MS revealed the spherical morphology and confirmed the particle size. In-vitro release showed that the CL release from CL-MS followed near zero–order drug release kinetics over nearly 1month. In-vivo pharmacokinetic study of CL-MS showed higher t1/2 (239±27.5h) compared to oily CL depot (32.7±4.8h) with sustained release of CL plasma concentration for 1month. The labile CL could thus be effectively encapsulated and protected against degradation during microspheres formulation, storage and release in presence of stabilizer. This novel CL loaded PLGA MS is stable and may have great potential for clinical use.

Graphical abstract

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From Oral Facial Dysfunction to Dysmorphism and the Onset of Pediatric OSA

The upper airway is a collapsible tube, and its collapsibility increases during sleep. Extrinsic factors such as atypical craniofacial features may increase the risks of airway collapse. We review early development of oral-facial structures and the anatomical variants that may be present at birth and can impact nasal breathing. After birth, there is a continuous interaction between orofacial functions and growth of anatomic features. We review the dysfunctions identified to date that may impact orofacial development leading to sleep-disordered-breathing through changes in the orofacial growth.

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A Phase II Multi‐Center Study of Bevacizumab in Combination with Ixabepilone in Subjects with Advanced Renal Cell Carcinoma

AbstractLessons Learned. Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments.The observation of three responses among the 30 patients with median progression‐free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development.Background.Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule‐stabilizing agent approved for the treatment of breast cancer, is active in taxane‐sensitive and ‐resistant cells. In this single‐arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC.Methods.We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)‐approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression‐free survival (PFS), overall survival (OS), and the toxicity of the combination.Results.The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2–54). The median follow‐up was 36.4 months (range 23.5–96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9–10.6) and the median OS was 15.0 months (95% CI, 11.3–28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%).Conclusion.The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second ‐ or later‐line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.

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Endogenous Heat‐Shock Protein Induction with or Without Radiofrequency Ablation or Cryoablation in Patients with Stage IV Melanoma

AbstractLessons Learned. Percutaneous thermal ablation combined with in situ granulocyte‐macrophage colony‐stimulating factor cytokine therapy was technically feasible and well tolerated.No significant clinical or immunologic responses were seen.Background.Melanoma tumor‐derived heat‐shock proteins (HSPs) and HSP‐peptide complexes can elicit protective antitumor responses. The granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) chemokine can also promote uptake and processing by professional antigen presenting cells (APCs). On this basis, we designed a pilot study of percutaneous thermal ablation as a means to induce heat‐shock protein vaccination plus GM‐CSF to determine safety and preliminary antitumor activity of this combination.Materials and Methods.This study was designed to assess overall safety of percutaneous ablation combined with GM‐CSF for unresectable, metastatic melanoma including uveal and mucosal types. All patients received heat‐shock therapy (42°C for 30 minutes), then received one of three treatments: (a) intralesional GM‐CSF (500 mcg standard dose); (b) radiofrequency ablation (RFA) + GM‐CSF; or (c) cryoablation plus GM‐CSF. The primary endpoint of the study was the induction of endogenous HSP70 and melanoma‐specific cytotoxic T lymphocytes (CTL).Results.Nine patients (three per study arm) were enrolled. No dose‐limiting toxicity was observed as specified per protocol. All patients developed progressive disease and went on to receive alternative therapy. Median overall survival (OS) was 8.2 months (95% confidence interval [CI] 2–17.2). The study was not powered to detect a difference in clinical outcome among treatment groups.Conclusion.Percutaneous thermal ablation plus GM‐CSF was well tolerated, technically feasible, and demonstrated an acceptable adverse event profile comparable to conventional RFA and cryoablation. While HSP70 was induced following therapy, the degree of HSP70 elevation was not associated with clinical outcome or induced CTL responses. While percutaneous thermal ablation plus GM‐CSF combinations including checkpoint inhibitors could be considered in future studies, the use of GM‐CSF remains experimental and for use in the context of clinical trials.

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The efficacy of plant extract and bioactive compounds approaches in the treatment of pulmonary fibrosis: A systematic review

Publication date: September 2017
Source:Biomedicine & Pharmacotherapy, Volume 93
Author(s): Sana Bahri, Ridha Ben Ali, Anouar Abidi, Saloua Jameleddine
Pulmonary fibrosis (PF) is a lethal, chronic and progressive respiratory disease leading to interstitial lung damage and serious breathing problems. The pathogenic mechanism involves activation, migration, proliferation and differentiation of fibroblasts into myofibroblats inducing extracellular matrix accumulation that destroy lung parenchyma. Available antifibrotic treatment options are limited to Pirfenidone and Nintedanib that prevent deterioration without an improvement of this disease. The use of plant extracts and natural bioactive compounds for the treatment of PF has been known for more than thirty years in China. Nowadays, phytotherapy has gained a considerable attention in the treatment of PF both in vivo and in vitro using bleomycin (BLM)-induced lung inflammation, oxidative stress and pulmonary fibrosis in rats. In this review, we aimed to focus on the protective effects and the mechanisms of action of several plant extracts described by various research works for the treatment of PF.

Graphical abstract

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Species diversity of remnant calcareous grasslands in south eastern Germany depends on litter cover and landscape structure

Publication date: August 2017
Source:Acta Oecologica, Volume 83
Author(s): Stephanie Huber, Birgit Huber, Silvia Stahl, Christoph Schmid, Christoph Reisch
Species diversity depends on, often interfering, multiple ecological drivers. Comprehensive approaches are hence needed to understand the mechanisms determining species diversity. In this study, we analysed the impact of vegetation structure, soil properties and fragmentation on the plant species diversity of remnant calcareous grasslands, therefore, in a comparative approach.We determined plant species diversity of 18 calcareous grasslands in south eastern Germany including all species and grassland specialists separately. Furthermore, we analysed the spatial structure of the grasslands as a result of fragmentation during the last 150 years (habitat area, distance to the nearest calcareous grassland and connectivity in 1830 and 2013). We also collected data concerning the vegetation structure (height of the vegetation, cover of bare soil, grass and litter) and the soil properties (content of phosphorous and potassium, ratio of carbon and nitrogen) of the grassland patches. Data were analysed using Bayesian multiple regressions.We observed a habitat loss of nearly 80% and increasing isolation between grasslands since 1830. In the Bayesian multiple regressions the species diversity of the studied grasslands depended negatively on cover of litter and to a lower degree on the distance to the nearest calcareous grassland in 2013, whereas soil properties had no significant impact.Our study supports the observation that vegetation structure, which strongly depends on land use, is often more important for the species richness of calcareous grasslands than fragmentation or soil properties. Even small and isolated grasslands may, therefore, contribute significantly to the conservation of species diversity, when they are still grazed.



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Human cells contain a factor that facilitates the DNA glycosylase-mediated excision of oxidized bases from occluded sites in nucleosomes.

Publication date: Available online 5 July 2017
Source:DNA Repair
Author(s): R.L. Maher, C.G. Marsden, A.M. Averil, S.S. Wallace, J.B. Sweasy, D.S. Pederson
Reactive oxygen species generate some 20,000 base lesions per human cell per day. The vast majority of these potentially mutagenic or cytotoxic lesions are subject to base excision repair (BER). Although chromatin remodelers have been shown to enhance the excision of oxidized bases from nucleosomes in vitro, it is not clear that they are recruited to and act at sites of BER in vivo. To test the hypothesis that cells possess factors that enhance BER in chromatin, we assessed the capacity of nuclear extracts from human cells to excise thymine glycol (Tg) lesions from exogenously added, model nucleosomes. The DNA glycosylase NTHL1 in these extracts was able to excise Tg from both naked DNA and sites in nucleosomes that earlier studies had shown to be sterically accessible. However, the same extracts were able to excise lesions from sterically-occluded sites in nucleosomes only after the addition of Mg²⁺/ATP. Gel mobility shift assays indicated that nucleosomes remain largely intact following the Mg²⁺/ATP −dependent excision reaction. Size exclusion chromatography indicated that the NTHL1-stimulating activity has a relatively low molecular weight, close to that of NTHL1 and other BER glycosylases; column fractions that contained the very large chromatin remodeling complexes did not exhibit this same stimulatory activity. These results indicate that cells possess a factor(s) that promotes the initiation of BER in chromatin, but differs from most known chromatin remodeling complexes.



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Corrigendum

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Tumor Targeting by Lentiviral Vectors Combined with Magnetic Nanoparticlesin Mice

Publication date: Available online 5 July 2017
Source:Acta Biomaterialia
Author(s): Ester Borroni, Marta Miola, Sara Ferraris, Giulia Ricci, Kristina ŽužekRožman, Nina Kostevšek, Angela Catizone, Lia Rimondini, Maria Prat, Enrica Verné, Antonia Follenzi
Nanomaterials conjugated or complexed with biological moieties such as antibodies, polymers or peptides appear to be suitable not only for drug delivery but also for specific cancer treatment. Here, biocompatible iron oxide magnetic nanoparticles (MNPs) with or without a silica shell coupled with lentiviral vectors (LVs) are proposed as a combined therapeutic approach to specifically target gene expression in a cancer mouse model. Initially, four different MNPs were synthesized and their physical properties were characterized to establish and discriminate their behaviors. MNPs and LVs strictly interacted and transduced cells in vitro as well as in vivo, with no toxicity or inflammatory responses. By injecting LV-MNPs complexes intravenously, green fluorescent protein (GFP) resulted in a sustained long-term expression. Furthermore, by applying a magnetic field on the abdomen of intravenous injected mice, GFP positive cells increased in livers and spleens.In liver, LV-MNPs were able to target both hepatocytes and non-parenchymal cells,while in a mouse model with a grafted tumor, intra-tumor LV-MNPsinjection and magnetic plaque application next to the tumor demonstrated the efficient uptake of LV-MNPs complexes with high number of transduced cells and iron accumulation in the tumor site. More important, LV-MNPs with the application of the magnetic plaque spread in all the tumor parenchyma and dissemination through the body was prevented confirming the efficient uptake of LV-MNPs complexes in the tumor. Thus, these LV-MNPs complexes could be used as multifunctional and efficient tools to selectively induce transgene expression in solid tumor for therapeutic purposes.Statement of SignificanceOur study describes a novel approach of combining magnetic properties of nanomaterials with gene therapy. Magnetic nanoparticles (MNPs) coated with or without a silica shell coupled with lentiviral vectors (LVs) were used as vehicle to target biological active molecules in a mouse cancer model. After in situ injection, the presence of MNP under the magnetic field improve the vector distribution in the tumor mass and after systemic administration, the application of the magnetic field favor targeting of specific organs for LV transduction and specifically can direct LV in specific cells (or avoiding them). Thus, our findings suggest that LV-MNPs complexes could be used as multifunctional and efficient tools to selectively induce transgene expression in solid tumor for therapeutic purposes.

Graphical abstract

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Bactericidal activity of self-assembled palmitic and stearic fatty acid crystals on highly ordered pyrolytic graphite

Publication date: Available online 5 July 2017
Source:Acta Biomaterialia
Author(s): Elena P. Ivanova, Song Ha Nguyen, Yachong Guo, Vladimir A. Baulin, Hayden K. Webb, Vi Khanh Truong, Jason V. Wandiyanto, Christopher J. Garvey, Peter J. Mahon, David E. Mainwaring, Russell J. Crawford
The wings of insects such as cicadas and dragonflies have been found to exhibit nanostructure arrays that are assembled from fatty acids, and that physically interact with and significantly disrupt bacterial cell membranes. Such mechanobactericidal surfaces are of significant interest, as they can kill bacteria without the need for antibacterial chemicals. Here, we report on the bactericidal effect of two main lipid components of insect wings epicuticle, palmitic (C16) and stearic (C18) fatty acid films after re-crystallisation on the surface of highly ordered pyrolytic graphite. It appeared that the presence of two additional CH2 groups resulted in the formation of different surface structures. Scanning electron microscopy and atomic force microscopy showed that palmitic acid microcrystallites were more asymmetric than those of stearic acid where the palmitic acid microcrystallites were observed as an angular abutment in the scanning electron micrographs. The principal differences between the two types of long-chain saturated fatty acids crystallites were the larger density of peaks in the upper contact plain of the palmitic acid crystallites as well as their greater proportion of asymmetrical shapes, in comparison to stearic acid. These two parameters might contribute to higher bactericidal activity on surfaces derived from palmitic acid. Both palmitic and stearic acid crystallised surfaces displayed bactericidal activity against Gram-negative, rod-shaped Pseudomonas aeruginosa and Gram-positive, spherical Staphylococcus aureus cells. These microcrystallite interfaces might be a useful tool in fabricating effective bactericidal nanocoatings.Statement of SignificanceNanostructured cicada and dragonfly wing surfaces have been discovered to be able physically kill bacterial cells. Here, we report on the successful fabrication of bactericidal three-dimensional structures of two main lipid components of insect wings epicuticule, palmitic (C16) and stearic (C18) fatty acids. Both palmitic and stearic acids after crystallisation on highly ordered pyrolytic graphite surfaces displayed bactericidal activity against both Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus cells. The simplicity of the production of these microcrystallite interfaces suggests that a fabrication technique based on solution deposition could be effectively applied to form bactericidal nanocoatings.

Graphical abstract

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Mussel-Inspired PLGA/polydopamine Core-shell Nanoparticle for Light Induced Cancer Thermochemotherapy

Publication date: Available online 5 July 2017
Source:Acta Biomaterialia
Author(s): Huacheng He, Eleni Markoutsa, Yihong Zhan, Jiajia Zhang, Peisheng Xu
Most photothermal converting systems are not biodegradable, which bring the uneasiness when they are administered into human body due to the uncertainty of their fate. Hereby, we developed a mussel-inspired PLGA/polydopamine core-shell nanoparticle for cancer photothermal and chemotherapy. With the help of an anti-EGFR antibody, the nanoparticle could effectively enter head and neck cancer cells and convert near-infrared light to heat to trigger drug release from PLGA core for chemotherapy as well as ablate tumors by the elevated temperature. Due to the unique nanoparticle concentration dependent peak working-temperature nature, an overheating or overburn situation can be easily prevented. Since the nanoparticle was retained in the tumor tissue and subsequently released its payload inside the cancer cells, no any doxorubicin-associated side effects were detected. Thus, the developed mussel-inspired PLGA/polydopamine core-shell nanoparticle could be a safe and effective tool for the treatment of head and neck cancer.Statement of significanceThe described EGFR targeted PLGA/polydopamine Core-shell Nanoparticle (PLGA/PD NP) is novel in the following aspectsDifferent from most photothermal converting nanomaterials, PLGA/PD NP is biodegradable, which eliminates the long-term safety concerns thwarting the clinical application of photothermal therapy.Different from most photothermal nanomaterials, upon NIR irradiation, PLGA/PD NP quickly heats its surrounding environment to a NP concentration dependent peak working temperature and uniquely keeps that temperature constant through the duration of light irradiation. Due to this unique property an overheating or overburn situation for the adjacent healthy tissue can be easily avoided.The PLGA/PD NP releases its payload through detaching PD shell under NIR laser irradiation.The EGFR-targeted doxorubicin-loaded PLGA/PD NP effectively eradicate head and neck tumorin vivo through the synergism of photothermal therapy and chemotherapy while not introducing doxorubicin associated cardiotoxicity.

Graphical abstract

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Manganese oxide particles as cytoprotective, oxygen generating agents

Publication date: Available online 5 July 2017
Source:Acta Biomaterialia
Author(s): Mohammad Hossein Tootoonchi, Mazdak Hashempour, Patricia L. Blackwelder, Christopher A. Fraker
Cell culture and cellular transplant therapies are adversely affected by oxidative species and radicals. Herein, we present the production of bioactive manganese oxide nanoparticles for the purpose of radical scavenging and cytoprotection. Manganese comprises the core active structure of somatic enzymes that perform the same function, in vivo. Formulated nanoparticles were characterized structurally and surveyed for maximal activity (superoxide scavenging, hydrogen peroxide scavenging with resultant oxygen generation) and minimal cytotoxicity (48-hour direct exposure to titrated manganese oxide concentrations). Cytoprotective capacity was tested using cell exposure to hydrogen peroxide in the presence or absence of the nanoparticles. Several ideal compounds were manufactured and utilized that showed complete disproportionation of superoxide produced by the xanthine/ xanthine oxidase reaction. Further, the nanoparticles showed catalase–like activity by completely converting hydrogen peroxide into the corresponding concentration of oxygen. Finally, the particles protected cells (murine ß-cell insulinoma) against insult from hydrogen peroxide exposure. Based on these observed properties, these particles could be utilized to combat oxidative stress and inflammatory response in a variety of cell therapy applications.Statement of significanceMaintaining viability once cells have been removed from their physiological niche, e.g. culture and transplant, demands proper control of critical variables such as oxygenation and removal of harmful substances e.g. reactive oxygen species. Limited catalysts can transform reactive oxygen species into molecular oxygen and, thereby, have the potential to maintain cell viability and function. Among these are manganese oxide particles which are the subject of this study.

Graphical abstract

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Effect of low-level laser-treated mesenchymal stem cells on myocardial infarction

Abstract

Cardiovascular disease is the leading cause of death worldwide. Although cardiac transplantation is considered the most effective therapy for end-stage cardiac diseases, it is limited by the availability of matching donors and the complications of the immune suppressive regimen used to prevent graft rejection. Application of stem cell therapy in experimental animal models was shown to reverse cardiac remodeling, attenuate cardiac fibrosis, improve heart functions, and stimulate angiogenesis. The efficacy of stem cell therapy can be amplified by low-level laser radiation. It is well established that the bio-stimulatory effect of low-level laser is influenced by the following parameters: wavelength, power density, duration, energy density, delivery time, and the type of irradiated target. In this review, we evaluate the available experimental data on treatment of myocardial infarction using low-level laser. Eligible papers were characterized as in vivo experimental studies that evaluated the use of low-level laser therapy on stem cells in order to attenuate myocardial infarction. The following descriptors were used separately and in combination: laser therapy, low-level laser, low-power laser, stem cell, and myocardial infarction. The assessed low-level laser parameters were wavelength (635–804 nm), power density (6–50 mW/cm²), duration (20–150 s), energy density (0.96–1 J/cm²), delivery time (20 min–3 weeks after myocardial infarction), and the type of irradiated target (bone marrow or in vitro-cultured bone marrow mesenchymal stem cells). The analysis focused on the cardioprotective effect of this form of therapy, the attenuation of scar tissue, and the enhancement of angiogenesis as primary targets. Other effects such as cell survival, cell differentiation, and homing are also included. Among the evaluated protocols using different parameters, the best outcome for treating myocardial infarction was achieved by treating the bone marrow by one dose of low-level laser with 804 nm wavelength and 1 J/cm² energy density within 4 h of the infarction. This approach increased stem cell survival, proliferation, and homing. It has also decreased the infarct size and cell apoptosis, leading to enhanced heart functions. These effects were stable for 6 weeks. However, more studies are still required to assess the effects of low-level laser on the genetic makeup of the cell, the nuclei, and the mitochondria of mesenchymal stromal cells (MSCs).

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Vertical gaze palsy due to acute bilateral thalamic infarct without midbrain ischemia

Shakya Bhattacharjee, Kher Lik Ng

Neurology India 2017 65(4):919-920



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A longitudinal clinicopathological study of two unrelated patients with Charcot–Marie–Tooth disease type 1E

Jee Young Kim, Sung-Hee Kim, Ji-Young Park, Haesoo Koo, Kee-Duk Park, Young Bin Hong, Ki Wha Chung, Byung-Ok Chot

Neurology India 2017 65(4):893-895



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The making of a complete neurosurgeon

K Ganapathy

Neurology India 2017 65(4):694-696



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Kleine–Levin syndrome: A neurological rarity

Samhita Panda

Neurology India 2017 65(4):873-878



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Dose fractionated gamma knife radiosurgery for large arteriovenous malformations

Ajay Niranjan, John C Flickinger

Neurology India 2017 65(4):697-698



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Recurrent brown tumor of the vertebral column

Michal Paradowski, Joanna Bladowska, Agnieszka Halon, Boguslaw Paradowski

Neurology India 2017 65(4):908-909



http://ift.tt/2srpSYN