SMC Progressively Aligns Chromosomal Arms in Caulobacter crescentus but Is Antagonized by Convergent Transcription

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Ngat T. Tran, Michael T. Laub, Tung B.K. Le
The structural maintenance of chromosomes (SMC) complex plays an important role in chromosome organization and segregation in most living organisms. In Caulobacter crescentus, SMC is required to align the left and the right arms of the chromosome that run in parallel down the long axis of the cell. However, the mechanism of SMC-mediated alignment of chromosomal arms remains elusive. Here, using genome-wide methods and microscopy of single cells, we show that Caulobacter SMC is recruited to the centromeric parS site and that SMC-mediated arm alignment depends on the chromosome-partitioning protein ParB. We provide evidence that SMC likely tethers the parS-proximal regions of the chromosomal arms together, promoting arm alignment. Furthermore, we show that highly transcribed genes near parS that are oriented against SMC translocation disrupt arm alignment, suggesting that head-on transcription interferes with SMC translocation. Our results demonstrate a tight interdependence of bacterial chromosome organization and global patterns of transcription.

Graphical abstract

Teaser

Tran et al. investigate the mechanism and function of SMC in the global organization of the Caulobacter chromosome. The findings suggest that SMC functions as a tether to actively cohese the chromosomal arms together and show that head-on transcription profoundly interferes with SMC translocation from the centromeric parS site.


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Feeling Stressed under the Sun? RPA1 Acetylation to the Rescue

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Debabrata Chakravarti, Tapas K. Hazra
Nucleotide excision repair (NER) requires replication protein A (RPA), among others, to respond to DNA damaging agents. In this issue of Cell Reports, He et al. (2017) and Zhao et al. (2017) show acetylation of RPA1 regulates the UV-induced DNA damage response.

Teaser

Nucleotide excision repair (NER) requires replication protein A (RPA), among others, to respond to DNA damaging agents. In this issue of Cell Reports, He et al. (2017) and Zhao et al. (2017) show acetylation of RPA1 regulates the UV-induced DNA damage response.


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Lysophosphatidic Acid Receptor 4 Activation Augments Drug Delivery in Tumors by Tightening Endothelial Cell-Cell Contact

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Kazuhiro Takara, Daisuke Eino, Koji Ando, Daisuke Yasuda, Hisamichi Naito, Yohei Tsukada, Tomohiro Iba, Taku Wakabayashi, Fumitaka Muramatsu, Hiroyasu Kidoya, Shigetomo Fukuhara, Naoki Mochizuki, Satoshi Ishii, Haruhiko Kishima, Nobuyuki Takakura
Vascular normalization in tumors may improve drug delivery and anti-tumor immunity. Angiogenesis inhibitors induce hypoxia, which may facilitate malignant progression; therefore, we investigated other methods to promote vascular maturation. Here, we show that lysophosphatidic acid (LPA) enhances blood flow by promoting fine vascular networks, thereby improving vascular permeability and suppressing tumor growth when combined with anti-cancer drug treatment. Six different G protein-coupled receptors have been identified as LPA receptors (LPA1–6). In studies using mutant mice, we found that LPA4 is involved in vascular network formation. LPA4 activation induces circumferential actin bundling beneath the cell membrane and enhances linear adherens junction formation by VE-cadherin in endothelial cells. Therefore, we conclude that activation of LPA4 is a promising approach for vascular regulation.

Graphical abstract

Teaser

Takara et al. find that lysophosphatidic acid (LPA) promotes fine capillary network formation and improves drug delivery in tumors. LPA controls localization of VE-cadherin in endothelial cells through LPA receptor 4 (LPA4) signaling.


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Spatiotemporal Control of Lipid Conversion, Actin-Based Mechanical Forces, and Curvature Sensors during Clathrin/AP-1-Coated Vesicle Biogenesis

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Mihaela Anitei, Christoph Stange, Cornelia Czupalla, Christian Niehage, Kai Schuhmann, Pia Sala, Aleksander Czogalla, Theresia Pursche, Ünal Coskun, Andrej Shevchenko, Bernard Hoflack
Clathrin/adaptor protein-1-coated carriers connect the secretory and the endocytic pathways. Carrier biogenesis relies on distinct protein networks changing membrane shape at the trans-Golgi network, each regulating coat assembly, F-actin-based mechanical forces, or the biophysical properties of lipid bilayers. How these different hubs are spatiotemporally coordinated remains largely unknown. Using in vitro reconstitution systems, quantitative proteomics, and lipidomics, as well as in vivo cell-based assays, we characterize the protein networks controlling membrane lipid composition, membrane shape, and carrier scission. These include PIP5K1A and phospholipase C-beta 3 controlling the conversion of PI[4]P into diacylglycerol. PIP5K1A binding to RAC1 provides a link to F-actin-based mechanical forces needed to tubulate membranes. Tubular membranes then recruit the BAR-domain-containing arfaptin-1/2 guiding carrier scission. These findings provide a framework for synchronizing the chemical/biophysical properties of lipid bilayers, F-actin-based mechanical forces, and the activity of proteins sensing membrane shape during clathrin/adaptor protein-1-coated carrier biogenesis.

Graphical abstract

Teaser

Clathrin/adaptor protein-1 (AP-1) coats control the transport of specific cargoes between the biosynthetic and endocytic pathways. Anitei et al. illustrate the coordination of protein networks controlling the biophysical properties of lipid bilayers, actin-based mechanical forces, and membrane curvature during clathrin/AP-1-coated carrier biogenesis.


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Aberrant Compartment Formation by HSPB2 Mislocalizes Lamin A and Compromises Nuclear Integrity and Function

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Federica F. Morelli, Dineke S. Verbeek, Jessika Bertacchini, Jonathan Vinet, Laura Mediani, Sandra Marmiroli, Giovanna Cenacchi, Milena Nasi, Sara De Biasi, Jeanette F. Brunsting, Jan Lammerding, Elena Pegoraro, Corrado Angelini, Rossella Tupler, Simon Alberti, Serena Carra
Small heat shock proteins (HSPBs) contain intrinsically disordered regions (IDRs), but the functions of these IDRs are still unknown. Here, we report that, in mammalian cells, HSPB2 phase separates to form nuclear compartments with liquid-like properties. We show that phase separation requires the disordered C-terminal domain of HSPB2. We further demonstrate that, in differentiating myoblasts, nuclear HSPB2 compartments sequester lamin A. Increasing the nuclear concentration of HSPB2 causes the formation of aberrant nuclear compartments that mislocalize lamin A and chromatin, with detrimental consequences for nuclear function and integrity. Importantly, phase separation of HSPB2 is regulated by HSPB3, but this ability is lost in two identified HSPB3 mutants that are associated with myopathy. Our results suggest that HSPB2 phase separation is involved in reorganizing the nucleoplasm during myoblast differentiation. Furthermore, these findings support the idea that aberrant HSPB2 phase separation, due to HSPB3 loss-of-function mutations, contributes to myopathy.

Graphical abstract

Teaser

Morelli et al. show that, in mammalian cells, HSPB2 forms liquid-like nuclear compartments that affect lamin A localization and mobility, with detrimental consequences for chromatin organization and nuclear integrity. Aberrant compartment formation by HSPB2 is regulated by HSPB3, but not by two identified HSPB3 mutants linked to myopathy.


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Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Laina Freyer, Chih-Wei Hsu, Sonja Nowotschin, Andrea Pauli, Junji Ishida, Keiji Kuba, Akiyoshi Fukamizu, Alexander F. Schier, Pamela A. Hoodless, Mary E. Dickinson, Anna-Katerina Hadjantonakis
Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to the appearance of physical malformations. Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos.

Graphical abstract

Teaser

Apela (a.k.a. Elabela, Ende, and Toddler) is a key signaling peptide that activates APLNR in mouse development. Freyer et al. show that lethal developmental defects in Apela mutants may rely on sufficient blood circulation. They suggest that extraembryonic mesoderm derivatives, including endothelial and hematopoietic progenitors, may be the first cell populations impacted by the loss of Apela.


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Folding of the Cerebral Cortex Requires Cdk5 in Upper-Layer Neurons in Gyrencephalic Mammals

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Yohei Shinmyo, Yukari Terashita, Tung Anh Dinh Duong, Toshihide Horiike, Muneo Kawasumi, Kazuyoshi Hosomichi, Atsushi Tajima, Hiroshi Kawasaki
Folds in the cerebral cortex in mammals are believed to be key structures for accommodating increased cortical neurons in the cranial cavity. However, the mechanisms underlying cortical folding remain largely unknown, mainly because genetic manipulations for the gyrencephalic brain have been unavailable. By combining in utero electroporation and the CRISPR/Cas9 system, we succeeded in efficient gene knockout of Cdk5, which is mutated in some patients with classical lissencephaly, in the gyrencephalic brains of ferrets. We show that Cdk5 knockout in the ferret cerebral cortex markedly impaired cortical folding. Furthermore, the results obtained from the introduction of dominant-negative Cdk5 into specific cortical layers suggest that Cdk5 function in upper-layer neurons is more important for cortical folding than that in lower-layer neurons. Cdk5 inhibition induced severe migration defects in cortical neurons. Taken together, our findings suggest that the appropriate positioning of upper-layer neurons is critical for cortical folding.

Graphical abstract

Teaser

Shinmyo et al. describe a highly efficient gene knockout method for the folded cerebral cortex of ferrets using the CRISPR/Cas9 system. Loss-of-function studies of the Cdk5 gene suggest that appropriate positioning of upper-layer neurons is crucial for cortical folding.


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A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Marlen Knobloch, Gregor-Alexander Pilz, Bart Ghesquière, Werner J. Kovacs, Thomas Wegleiter, Darcie L. Moore, Martina Hruzova, Nicola Zamboni, Peter Carmeliet, Sebastian Jessberger
Hippocampal neurogenesis is important for certain forms of cognition, and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. Here, we show that the rate of fatty acid oxidation (FAO) regulates the activity of NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.

Graphical abstract

Teaser

Controlled balance between proliferation and quiescence of neural stem/progenitor cells (NSPCs) is required for lifelong neurogenesis. Knobloch et al. identify a metabolic shift in fatty acid oxidation (FAO) that governs the proliferation of NSPCs. Further, their data suggest an instructive role for FAO in regulating NSPC activity. Thus, Knobloch et al. identify FAO as a key metabolic pathway to regulate NSPC activity.


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Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Megan S. Wyeth, Kenneth A. Pelkey, Xiaoqing Yuan, Geoffrey Vargish, April D. Johnston, Steven Hunt, Calvin Fang, Daniel Abebe, Vivek Mahadevan, André Fisahn, Michael W. Salter, Roderick R. McInnes, Ramesh Chittajallu, Chris J. McBain
Although Netos are considered auxiliary subunits critical for kainate receptor (KAR) function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM)-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1)-, and parvalbumin (PV)-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.

Graphical abstract

Teaser

Netos are considered critical kainate receptor (KAR) auxiliary subunits in glutamatergic principal cells, but their roles in GABAergic interneurons remain unexplored. Wyeth et al. find that somatodendritic KARs within diverse interneurons require Neto1, whereas both Neto1 and Neto2 regulate presynaptic KAR-mediated suppression of inhibitory transmission.


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The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Jui-Heng Tseng, Ling Xie, Sheng Song, Youmei Xie, Lauren Allen, Deepa Ajit, Jau-Shyong Hong, Xian Chen, Rick B. Meeker, Todd J. Cohen
The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.

Graphical abstract

Teaser

Tau mislocalization and aggregation are implicated in the pathogenesis of Alzheimer's disease. Tseng et al. report that endogenous neuronal tau re-localizes to distinct neuritic foci, which are active sites of calcium deregulation, leading to aberrant tau accumulation. These findings provide insights into the early-stage tau dysfunction that occurs in vulnerable neurons.


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Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Xiaowan Wang, Qiao Zhang, Ruisi Bao, Nannan Zhang, Yingzhen Wang, Luis Polo-Parada, Andrew Tarim, Aidan Alemifar, Xianlin Han, Heather M. Wilkins, Russell H. Swerdlow, Xinglong Wang, Shinghua Ding
Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD⁺ biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD⁺ biosynthesis pathway is a potential therapeutic target for degenerative MN diseases.

Graphical abstract

Teaser

Wang et al. find that projection neuron NAMPT is essential for mitochondrial bioenergetics, motor function, and survival of adult mice and that iNAMPT is reduced in ALS patients. NMN improves health and extends the lifespan of Nampt knockout mice. Their findings suggest therapeutic avenues for motor neuron degenerative diseases.


http://ift.tt/2wgz1rn

Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Theodoros I. Roumeliotis, Steven P. Williams, Emanuel Gonçalves, Clara Alsinet, Martin Del Castillo Velasco-Herrera, Nanne Aben, Fatemeh Zamanzad Ghavidel, Magali Michaut, Michael Schubert, Stacey Price, James C. Wright, Lu Yu, Mi Yang, Rodrigo Dienstmann, Justin Guinney, Pedro Beltrao, Alvis Brazma, Mercedes Pardo, Oliver Stegle, David J. Adams, Lodewyk Wessels, Julio Saez-Rodriguez, Ultan McDermott, Jyoti S. Choudhary
Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.

Graphical abstract

Teaser

Roumeliotis et al. use in-depth proteomics to assess the impact of genomic alterations on protein networks in colorectal cancer cell lines. Cell-line-specific network signatures are inferred de novo by protein quantification profiles and ultimately expose the collateral and transcript-independent effects of detrimental mutations on protein complexes.


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The Functional Impact of Alternative Splicing in Cancer

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Héctor Climente-González, Eduard Porta-Pardo, Adam Godzik, Eduardo Eyras
Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remain mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis revealed that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors and potentially disrupt protein-protein interactions in cancer-related pathways. Moreover, there was a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors may represent independent oncogenic processes that could be relevant to explain the functional transformations in cancer, and some of them could potentially be considered alternative splicing drivers (AS drivers).

Graphical abstract

Teaser

Climente-González et al. show that alternative splicing (AS) changes in tumors are linked to a significant loss of functional domain families that are also frequently mutated in cancer. These domain losses happen independently of somatic mutations and lead to the remodeling of complexes and protein-protein interactions in cancer.


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Generation of Mouse Haploid Somatic Cells by Small Molecules for Genome-wide Genetic Screening

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Zheng-Quan He, Bao-Long Xia, Yu-Kai Wang, Jing Li, Gui-Hai Feng, Lin-Lin Zhang, Yu-Huan Li, Hai-Feng Wan, Tian-Da Li, Kai Xu, Xue-Wei Yuan, Yu-Fei Li, Xin-Xin Zhang, Ying Zhang, Liu Wang, Wei Li, Qi Zhou
The recent success of derivation of mammalian haploid embryonic stem cells (haESCs) has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons. Using piggyBac transposon-based insertional mutagenesis, we generated a haploid neural cell library harboring genome-wide mutations for genetic screening. As a proof of concept, we screened for Mn²⁺-mediated toxicity and identified the Park2 gene. Our findings expand the applications of mouse haploid cell technology to somatic cell types and may also shed light on the mechanisms of ploidy maintenance.

Graphical abstract

Teaser

He et al. show that CDK1 and ROCK inhibition can suppress the spontaneous diploidization of haploid embryonic stem cells (haESCs) and generate haploid somatic cells of all three germ layers for genome-wide genetic screening.


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Mass Cytometry and Topological Data Analysis Reveal Immune Parameters Associated with Complications after Allogeneic Stem Cell Transplantation

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Tadepally Lakshmikanth, Axel Olin, Yang Chen, Jaromir Mikes, Erik Fredlund, Mats Remberger, Brigitta Omazic, Petter Brodin
Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.

Graphical abstract

Teaser

Lakshmikanth et al. conduct a systems analysis of immune reconstitution after stem cell transplantation. Using topological data analysis, combinations of cells and proteins associated with CMV and graft-versus-host disease were revealed and illustrate the potential of systems immunomonitoring to improve the development and evaluation of cancer immunotherapies.


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Systems Vaccinology Identifies an Early Innate Immune Signature as a Correlate of Antibody Responses to the Ebola Vaccine rVSV-ZEBOV

Publication date: 29 August 2017
Source:Cell Reports, Volume 20, Issue 9
Author(s): Anne Rechtien, Laura Richert, Hadrien Lorenzo, Gloria Martrus, Boris Hejblum, Christine Dahlke, Rahel Kasonta, Madeleine Zinser, Hans Stubbe, Urte Matschl, Ansgar Lohse, Verena Krähling, Markus Eickmann, Stephan Becker, Rodolphe Thiébaut, Marcus Altfeld, Marylyn Addo
Predicting vaccine efficacy remains a challenge. We used a systems vaccinology approach to identify early innate immune correlates of antibody induction in humans receiving the Ebola vaccine rVSV-ZEBOV. Blood samples from days 0, 1, 3, 7, and 14 were analyzed for changes in cytokine levels, innate immune cell subsets, and gene expression. Integrative statistical analyses with cross-validation identified a signature of 5 early innate markers correlating with antibody titers on day 28 and beyond. Among those, IP-10 on day 3 and MFI of CXCR6 on NK cells on day 1 were independent correlates. Consistently, we found an early gene expression signature linked to IP-10. This comprehensive characterization of early innate immune responses to the rVSV-ZEBOV vaccine in humans revealed immune signatures linked to IP-10. These results suggest correlates of vaccine-induced antibody induction and provide a rationale to explore strategies for augmenting the effectiveness of vaccines through manipulation of IP-10.

Graphical abstract

Teaser

Rechtien et al. apply a systems vaccinology approach to examine the early innate immune responses elicited by the Ebola vaccine rVSV-ZEBOV. They find that early innate immune responses, with IP-10 as an independent soluble marker, correlate with EBOV-GP-specific antibody induction.


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Blowing the Whistle; the Ethical, Professional and Legal Implications of Raising Concerns and Self-Regulation within Dentistry

Abstract

Whistle-blowers are a necessary part of any system; dentistry is no different. The role of whistle-blowers in dentistry has been enshrined in Australian law since 2010. Raising concerns has become a legal duty as well as an ethical and professional obligation. It is important that these different aspects of raising concerns are explored as each adds another layer of consideration to the issue. The health professional's duty to whistle-blow could be viewed as problematic; the observance of this duty is associated with being trapped between a rock and a hard place where any decision to engage or not may have negative consequences. For the obligation of raising concerns to gain acceptability within the dental profession, the concept requires reframing as being necessary for the profession's continued success. The stigma of mandatory reporting needs to be removed to allow this essential process to occur. This article will discuss the ethical, professional and legal imperatives for the dental profession to engage with whistle-blowing and the likely challenges that are likely to be met in doing so.

This article is protected by copyright. All rights reserved.

http://ift.tt/2wHdauk

Prosthodontic management of maxillofacial cases: a case series

Abstract

Maxillo-facial prosthetics is an important and recognised sub-discipline of prosthodontics that forms a key component of postgraduate training programs. General dentists have a role to play in the management of maxillo-facial defect patients even though treatment usually requires a multidisciplinary approach in an institutional environment. Maxillo-facial prosthetic cases frequently present with complex histories but simple patient goals. The conservatively managed implant-retained auricular prosthesis, speech aid prosthesis and orbital prosthesis cases described in this report were completed in a postgraduate clinical residency program and highlight the intrinsic complexities, challenges and ultimately satisfaction related to cases of this nature.

This article is protected by copyright. All rights reserved.

http://ift.tt/2wm6XRH

Oral health of community dwelling older Australian men: The Concord Health and Ageing in Men Project (CHAMP)

Abstract

Background

CHAMP is a cohort study of the health of a representative sample of Australian men aged 70 years and older. The aim of this report is to describe the oral health of these men.

Methods

Oral health was assessed when the men were all aged 78 years or older. Two calibrated examiners conducted a standardised intra-oral assessment. Descriptive data, with means and confidence intervals where appropriate, were analysed by statistical association tests. Participants were excluded from the collection of some periodontal assessments if they had a medical contraindication.

Results

Dental assessments of 614 participants revealed 90 (14.6%) were edentate. Men had a mean of 13.8 (CI 13.2-14.4) missing teeth and 10.3 (CI 9.8-10.8)teeth. Dentate participants had a mean of 1.1(CI 0.9-1.2) teeth with active coronal decay. Participants born in Italy had higher rates of sound teeth and lower rates of filled teeth, while those in the low income group had a higher rate of decayed teeth and lower rate of filled teeth. Thirty-four participants (5.5%) had one or more dental implants, and 66.3%relied on substitute natural teeth for functional occlusion. Of the 296 participants with full periodontal assessments, 90.9% (n=269) had one or more sites with pocket depths ≥3mm, 96.6% (n=286), had one or more sites with clinical attachment loss ≥ 5mm and 90.2% (n=267) had three or more sites with GI ≥ 2 scores.

Conclusions

There was a high prevalence of periodontal diseases and restorative burden of dentitions, which suggests that greater attention needs to be given to prevention and health maintenance in older Australian men.

This article is protected by copyright. All rights reserved.

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Studying the human oral microbiome: challenges and the evolution of solutions

Abstract

Since the pioneering work of van Leeuwenhoek in 1684, subsequently built upon by other renowned microbiologists Robert Koch, Willoughby Miller and G.V. Black, oral microbiology has developed innovative techniques to study the oral microflora (now termed the "oral microbiome"). The advent of molecular techniques such as DNA-DNA hybridisation, polymerase chain reaction (PCR) and DNA sequencing has created an array of opportunities to construct a comprehensive picture of the diversity and composition of the oral microbiome. Approximately 700 oral bacterial species have been identified, of which 50% have yet to be cultivated, and some of these are known only by their signature DNA sequences. The synergism of ever-evolving culture-based and state-of-the-art culture-independent molecular techniques has facilitated in-depth understanding of the dynamics, acquisition and transfer of oral bacteria, along with their role in oral and general health and disease. Further research is needed to not only analyse but also to make sense of the ever-increasing volumes of data which these molecular techniques (especially high-throughput DNA sequencing) are generating, as well as why particular bacteria are present and what they are "actually doing" there. This review presents a comprehensive literature search of oral microbiology-related methods currently used to study the oral microbiome.

This article is protected by copyright. All rights reserved.

http://ift.tt/2wmq4er

In the Hunger Games, the Winner Takes Everything

Publication date: Available online 28 August 2017
Source:Trends in Biochemical Sciences
Author(s): Franziska Püschel, Cristina Muñoz-Pinedo
Entosis is an atypical form of cell death that occurs when a cell engulfs and kills another cell. A recent article by Overholtzer and colleagues indicates that glucose deprivation promotes entosis. AMP-activated protein kinase (AMPK) activation in the loser cells triggers their engulfment and elimination by winner cells, which endure starvation.



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Effects of Cataract Opacity and Surgery on Sleep Quality

Rejuvenation Research , Vol. 0, No. 0.


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Scholar : These new articles for Annals of the American Association of Geographers are available online

The online platform for Taylor & Francis Online content New for Annals of the American Association of Geographers and online now on Taylor & Francis Online: Articles Elemental Aesthetics: On Artistic Experiments with Solar Energy Sasha Engelmann & Derek McCormack Pages: 1-19 | DOI: 10.1080/24694452.2017.1353901 The Geographical Legacies of Mountains: Impacts on Cultural Difference Landscapes Wenjie Wu, Jianghao Wang , Tianshi Dai & Xin (Mark) Wang Pages: 1-14 | DOI: 10.1080/24694452.2017.1352481 Transnational Suburbia: Spatialities of Gated Suburbs and Filipino Diaspora in Manila's Periurban Fringe Arnisson Andre C. Ortega Pages: 1-19 | DOI: 10.1080/24694452.2017.1352482 Methods, Models, and GIS Multiscale Geographically Weighted Regression (MGWR) A. Stewart Fotheringham, Wenbai Yang & Wei Kang Pages: 1-19 | DOI: 10.1080/24694452.2017.1352480 Interested in the political-economic topics surrounding China? You wouldn't want to miss this exclusive collection. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Thyroid diseases and bone health

Abstract

Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength.

http://ift.tt/2wgdYVX

Deiodinases and stem cells: an intimate relationship

Abstract

Thyroid hormone is a major determinant of tissue functions in vivo. The deiodinase family controls the tissue-specific activation or inactivation of intracellular thyroid hormones. Precise control of the T3-dependent transcriptional program is required by multiple cell systems, including the stem cell. In this context, the identification of a close connection between thyroid hormones and different signal pathways involved in the control of stem cell functions suggested that the deiodinases may play a role in the definition of stem cell biology and physiology. Stem cells have an unlimited self-renewal capacity and the potential to differentiate into different types of mature cells. Deciphering how all these events are achieved, how the T3 signal is controlled and integrated in stem cells and their niches, and how it can impact on them is essentially unknown and represents a challenge for coming years. In this review, I will explore the role played by the deiodinases in the modulation of the TH signal in stem cells of adult tissues, namely muscle and intestine, and how their actions control the delicate balance among self-renewal, proliferation and differentiation. Elucidation of the molecular mechanisms presiding thyroid hormone action in stem cells may reveal therapeutic potential, for example in the fields of regenerative diseases and cancer.

http://ift.tt/2xuHCFx

Dermoscopy prior to Mohs Micrographic surgery does not improve tumour margin assessment and lead to fewer Mohs stages

Abstract

Dermoscopy prior to Mohs Micrographic surgery does not improve tumour margin assessment for basal cell carcinoma of the head and neck and lead to fewer Mohs stages Mohs micrographic surgery (MMS) is a time consuming and expensive gold standard treatment for difficult to treat basal cell carcinoma (BCC). One factor that contributes significantly to the expense and duration is the number of stages required to obtain clear excision margins.

This article is protected by copyright. All rights reserved.

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Scholar : These new articles for Archives and Records are available online

The online platform for Taylor & Francis Online content New for Archives and Records and online now on Taylor & Francis Online: Original Articles Restor(y)ing community identity through the archive of Ken Saro-Wiwa Vanessa Louise Platt Pages: 1-19 | DOI: 10.1080/23257962.2017.1363032 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Contribution of the ENT (Ear, Nose, and Throat) Surgeon's Clinical Evaluation to the Contouring of Target Volumes and Organs Eligible for Radiotherapy in Head and Neck Cancers

Conditions:   Radiotherapy, Conformal (IMRT);   Head and Neck Cancer;   Otolaryngology;   Surgeons;   Radiation Oncologists
Intervention:   Other: Systematic consideration of the advice of the ENT surgeon in the determination of the radiotherapy target volumes in head and neck cancers.
Sponsor:   Fondation Ophtalmologique Adolphe de Rothschild
Not yet recruiting - verified July 2017

http://ift.tt/2xuQI4X

Familial Investigations of Childhood Cancer Predisposition

Conditions:   Acute Leukemia;   Adenomatous Polyposis;   Adrenocortical Carcinoma;   AML;   BAP1 Tumor Predisposition Syndrome;   Carney Complex;   Choroid Plexus Carcinoma;   Constitutional Mismatch Repair Deficiency Syndrome;   Diamond-Blackfan Anemia;   DICER1 Syndrome;   Dyskeratosis Congenita;   Emberger Syndrome;   Familial Acute Myeloid Leukaemia;   Familial Adenomatous Polyposis;   Fanconi Anemia;   Familial Cancer;   Familial Wilms Tumor;   Familial Neuroblastoma;   GIST;   Hereditary Breast and Ovarian Cancer;   Hereditary Paraganglioma-Pheochromocytoma Syndrome;   Hodgkin Lymphoma;   Juvenile Polyposis;   Li-Fraumeni Syndrome;   Lynch Syndrome;   MDS;   Melanoma Syndrome;   Multiple Endocrine Neoplasia Type 1;   Multiple Endocrine Neoplasia Type 2;   Neuroblastoma;   Neurofibromatosis Type 1;   Neurofibromatosis Type II;   Nevoid Basal Cell Carcinoma Syndrome;   Non Hodgkin Lymphoma;   Noonan Syndrome and Other Rasopathy;   Overgrowth Syndromes;   Pancreatic Cancer;   Peutz-Jeghers Syndrome;   Pheochromocytoma/Paraganglioma;   PTEN Hamartoma Tumor Syndrome;   Retinoblastoma;   Rhabdoid Tumor Predisposition Syndrome;   Rhabdomyosarcoma;   Rothmund-Thomson Syndrome;   Tuberous Sclerosis;   Von Hippel-Lindau Disease
Intervention:  
Sponsor:   St. Jude Children's Research Hospital
Recruiting - verified August 2017

http://ift.tt/2wf1Nss

Evaluation of Video Laryngoscopy in Patients With Head and Neck Pathology

Condition:   Difficult Intubation
Intervention:   Device: Indirect Laryngoscopy
Sponsor:   Icahn School of Medicine at Mount Sinai
Recruiting - verified August 2017

http://ift.tt/2wffEz7

Expressing Personalized Tumor Antigens Study

Conditions:   Colon Cancer Metastatic;   Head and Neck Cancer Metastatic;   Metastatic Non-Small Cell Lung Cancer
Intervention:   Biological: ADXS-NEO
Sponsors:   Advaxis, Inc.;   Amgen
Not yet recruiting - verified August 2017

http://ift.tt/2xuF8qA

The role of radical radiotherapy in the management of malignant pleural mesothelioma: A systematic review

Publication date: Available online 28 August 2017
Source:Radiotherapy and Oncology
Author(s): Miranda Ashton, Noelle O'Rourke, Suzanne Currie, Andreas Rimner, Anthony Chalmers
Malignant pleural mesothelioma (MPM) is a devastating disease with limited treatment options and a dismal prognosis. Attempts to employ radical radiotherapy in this disease have been limited by the complex shape of the pleura and the dose restrictions necessitated by the close proximity of radiosensitive structures. Recent shifts towards a 'lung sparing' surgical approach in MPM have further heightened these challenges. The aim of this systematic review is to assess recent advances in radiotherapy planning and delivery, to ascertain how these developments have impacted on the feasibility of delivering photon-based, high-dose radiotherapy with radical intent in MPM. Three electronic databases were searched and a total of 249 articles reviewed. The challenge of generating high quality, practice-defining data for diseases such as MPM was highlighted by the identification of just two randomised studies. Much of the literature consisted of low quality, retrospective data with small cohorts and inconsistent reporting on radiotherapy techniques and dosimetry. Nevertheless, a number of prospective phase II studies were identified to suggest that radical doses of radiotherapy can be delivered safely after a lung sparing procedure in MPM, reporting encouraging survival data and acceptable levels of toxicity.



http://ift.tt/2vFTNgu

Evaluation of high dose volumetric CT to reduce inter-observer delineation variability and PTV margins for prostate cancer radiotherapy

Publication date: Available online 28 August 2017
Source:Radiotherapy and Oncology
Author(s): Hamideh Alasti, Young-Bin Cho, Charles Catton, Alejandro Berlin, Peter Chung, Andrew Bayley, Aaron Vandermeer, Vickie Kong, David Jaffray
PurposeThe aim was to determine whether the enhanced soft tissue contrast provided by high-dose volumetric CT (HDVCT) can reduce inter-observer variability in delineating prostate compared to helical conventional CT (CCT) scans and 3T MRI scans for patients undergoing radical prostate cancer radiotherapy. Secondly, to quantify the potential PTV reduction with decreased inter-observer variability.Materials and methodsA 320 slice volumetric CT scanner was used. The wide-detector coverage of 16cm enabled volumetric image acquisition of prostate gland in one rotation. Three imaging studies were performed on ten patients. CCT and HDVCT were performed consecutively at the same coordinate system followed by MRI. Five radiation oncologists delineated the prostate.ResultsThe inter-observer variability is 2.0±0.6, 1.9±0.4 and 1.8±0.4mm for CCT, HDVCT and MR respectively with the maximum at the apex region. Comparing inter-observer difference variability between CCT and HDVCT with MR indicates that observers have larger variations in contouring using CCT than HDVCT especially at apex. Jaccard index of HDVCT is significantly higher than CCT with a mean difference of 0.03 (p=0.011). Both MRI and HDVCT provide the opportunity for a 2mm PTV margin reduction at the apex compared to CCT.ConclusionInter-observer variability in delineation remains an important source of systematic error. HDCTV for treatment planning reduces this error without recourse to MRI and permits a PTV reduction of 2mm at the apex. The margins required to account for residual error with any imaging modality are still greater than are used in typical current practice.



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Developing a multidisciplinary rehabilitation package following hip fracture and testing in a randomised feasibility study: Fracture in the Elderly Multidisciplinary Rehabilitation (FEMuR).

A multidisciplinary rehabilitation package was developed for use following hip fracture and a feasibility randomised controlled trial identified methods for definitive evaluation.

http://ift.tt/2wlkEjS

Fentanyl (Fentora) [Internet].

The objective of this review was to perform a systematic review of the beneficial and harmful effects of Fentora for the management of breakthrough pain in cancer patients aged 18 years and older who are already receiving and who are tolerant to continuous opioid therapy for their persistent baseline cancer pain.

http://ift.tt/2wG9atW

Pilot of a randomised controlled trial of the selective serotonin reuptake inhibitor sertraline versus cognitive behavioural therapy for anxiety symptoms in people with generalised anxiety disorder who have failed to respond to low-intensity psychological treatments as defined by the National Institute for Health and Care Excellence guidelines.

Significant recruitment challenges led to premature closure of this trial for generalised anxiety disorder, and recruiting participants from primary care rather than psychological therapy services may be more successful.

http://ift.tt/2wlkDfO

Immunologic properties and therapeutic efficacy of a multivalent epitope-based vaccine against four Helicobacter pylori adhesins (urease, Lpp20, HpaA, and CagL) in Mongolian gerbils

Abstract

Background

Therapeutic vaccination is a desirable alternative for controlling Helicobacter pylori (H. pylori) infection. Attachment to the gastric mucosa is the first step in establishing bacterial colonization, and adhesins, which are on the surface of H. pylori, play a pivotal role in binding to human gastric mucosa.

Materials and Methods

In the present study, we constructed a multivalent epitope-based vaccine named CFAdE with seven carefully selected antigenic fragments from four H. pylori adhesins (urease, Lpp20, HpaA and CagL). The specificity, immunogenicity and ability to produce neutralizing antibodies of CFAdE were evaluated in BALB/c mice. After that, its therapeutic efficacy and protective immune mechanisms were explored in H. pylori-infected Mongolian gerbils.

Results

The results indicated that CFAdE could induce comparatively high levels of specific antibodies against urease, Lpp20, HpaA and CagL. Additionally, oral therapeutic immunization with CFAdE plus polysaccharide adjuvant (PA) significantly decreased H. pylori colonization compared with oral immunization with urease plus PA, and the protection was correlated with IgG and sIgA antibody and antigen-specific CD4⁺ T cells.

Conclusions

This study indicated that the multivalent epitope-based vaccine, which targeted multiple adhesins in adherence of H. pylori to the gastric mucosa, is more effective than the univalent vaccine targeting urease only. This multivalent epitope-based vaccine may be a promising therapeutic candidate vaccine against H. pylori infection.

http://ift.tt/2vodq1y

Scholar : These new articles for Criminal Justice Studies are available online

The online platform for Taylor & Francis Online content New for Criminal Justice Studies and online now on Taylor & Francis Online: Original Articles A three-year recidivism analysis of state correctional releases Kristen M. Zgoba & Laura M. Salerno Pages: 1-15 | DOI: 10.1080/1478601X.2017.1364641 Research note: career stage and job satisfaction among southern correctional officers Nancy L. Hogan, Eric G. Lambert, Bitna Kim, Michael Mendenhall, Kelly Cheeseman & Marie Griffin Pages: 1-12 | DOI: 10.1080/1478601X.2017.1370710 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : Amyloid, Volume 24, Issue 3, September 2017 is now available online on Taylor & Francis Online

The online platform for Taylor & Francis Online content Amyloid, Volume 24, Issue 3, September 2017 is now available online on Taylor & Francis Online. This new issue contains the following articles: Commentary Artificial neural network modelling of ATTR amyloidosis: is now the time? John L. Berk Pages: 141-142 | DOI: 10.1080/13506129.2017.1345732 Review Article Mining databases for protein aggregation: a review Paraskevi L. Tsiolaki , Katerina C. Nastou , Stavros J. Hamodrakas & Vassiliki A. Iconomidou Pages: 143-152 | DOI: 10.1080/13506129.2017.1353966 Original Article Applying an artificial neural network model for developing a severity score for patients with hereditary amyloid polyneuropathy Shenia Novis, Felipe Machado, Victor B. Costa, Debora Foguel, Marcia W. Cruz & José Manoel de Seixas Pages: 153-161 | DOI: 10.1080/13506129.2017.1343714 Changing epidemiology of AA amyloidosis: clinical observations over 25 years at a single national referral centre Thirusha Lane, Jennifer H. Pinney, Janet A. Gilbertson, David F. Hutt, Dorota M. Rowczenio, Shameem Mahmood, Sajitha Sachchithanantham, Marianna Fontana, Taryn Youngstein, Candida C. Quarta, Ashutosh D. Wechalekar, Julian D. Gillmore, Philip N. Hawkins & Helen J. Lachmann Pages: 162-166 | DOI: 10.1080/13506129.2017.1342235 Towards the improvement in stability of an anti-Aβ single-chain variable fragment, scFv-h3D6, as a way to enhance its therapeutic potential Laia Montoliu-Gaya, Javier Murciano-Calles, Jose C. Martinez & Sandra Villegas Pages: 167-175 | DOI: 10.1080/13506129.2017.1348347 Kidney biopsy in AA amyloidosis: impact of histopathology on prognosis Zeynep Kendi Celebi, Saba Kiremitci, Bengi Ozturk, Serkan Akturk, Siyar Erdogmus, Neval Duman, Kenan Ates, Sehsuvar Erturk, Gokhan Nergizoglu, Sim Kutlay, Sule Sengul, Arzu Ensari & Kenan Keven Pages: 176-182 | DOI: 10.1080/13506129.2017.1350158 Predictors of early treatment failure following initial therapy for systemic immunoglobulin light-chain amyloidosis Nidhi Tandon , Surbhi Sidana, S. Vincent Rajkumar, Angela Dispenzieri, Morie A. Gertz, Martha Q. Lacy, Robert A. Kyle, Francis K. Buadi, David Dingli, Suzanne R. Hayman, Amie L. Fonder, Miriam A. Hobbs, Wilson I. Gonsalves, Prashant Kapoor, Yi Lisa Hwa, Nelson Leung, Ronald S. Go, John A. Lust, Stephen J. Russell, Steven R. Zeldenrust & Shaji K. Kumar Pages: 183-188 | DOI: 10.1080/13506129.2017.1351354 Safety and efficacy of empirical interleukin-1 inhibition using anakinra in AA amyloidosis of uncertain aetiology Thirusha Lane, Ashutosh D. Wechalekar, Julian D. Gillmore, Philip N. Hawkins & Helen J. Lachmann Pages: 189-193 | DOI: 10.1080/13506129.2017.1352503 Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years | Fabio A. Barroso, Daniel P. Judge, Ben Ebede, Huihua Li, Michelle Stewart, Leslie Amass & Marla B. Sultan Pages: 194-204 | DOI: 10.1080/13506129.2017.1357545 Novel pathologic scoring tools predict end-stage kidney disease in light chain (AL) amyloidosis Samuel Rubinstein, Robert F. Cornell, Liping Du, Beatrice Concepcion, Stacey Goodman, Shelton Harrell, Sara Horst, Daniel Lenihan, David Slosky, Agnes Fogo & Anthony Langone Pages: 205-211 | DOI: 10.1080/13506129.2017.1360272 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : Acta Oncologica, Volume 56, Issue 9, September 2017 is now available online on Taylor & Francis Online

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The online platform for Taylor & Francis Online content Acta Oncologica, Volume 56, Issue 9, September 2017 is now available online on Taylor & Francis Online. This new issue contains the following articles: EDITORIAL What conclusions can be drawn from the Stockholm III rectal cancer trial in the era of watch and wait? B. Glimelius & A. Martling Pages: 1139-1142 | DOI: 10.1080/0284186X.2017.1344359 REVIEW Dose intense, dose dense and tailored dose adjuvant chemotherapy for early breast cancer: an evolution of concepts Alexios Matikas, Theodoros Foukakis & Jonas Bergh Pages: 1143-1151 | DOI: 10.1080/0284186X.2017.1329593 LETTER TO THE EDITOR The feasibility of short-course radiotherapy in a watch-and-wait policy for rectal cancer K. Bujko, L. Pietrzak, M. Partycki, M. Szczepkowski, L. Wyrwicz, M. Rupiński, A. Rutkowski & A. Mróz Pages: 1152-1154 | DOI: 10.1080/0284186X.2017.1327721 ORIGINAL ARTICLES: BREAST CANCER Validity of Danish Breast Cancer Group (DBCG) registry data used in the predictors of breast cancer recurrence (ProBeCaRe) premenopausal breast cancer cohort study Deirdre P. Cronin-Fenton, Anders Kjærsgaard, Thomas P. Ahern, Marco Mele, Marianne Ewertz, Stephen Hamilton-Dutoit, Peer M. Christiansen, Bent Ejlertsen, Henrik T. Sørensen, Timothy L. Lash & Rebecca A. Silliman Pages: 1155-1160 | DOI: 10.1080/0284186X.2017.1327720 A high level of estrogen-stimulated proteins selects breast cancer patients treated with adjuvant endocrine therapy with good prognosis Katrine L. H. Weischenfeldt, Tove Kirkegaard, Birgitte B. Rasmussen, Anita Giobbie-Hurder, Maj-Britt Jensen, Bent Ejlertsen & Anne E. Lykkesfeldt Pages: 1161-1167 | DOI: 10.1080/0284186X.2017.1324211 The will to live – breast cancer patients perceptions' of palliative chemotherapy Jenny Bergqvist & Peter Strang Pages: 1168-1174 | DOI: 10.1080/0284186X.2017.1327719 ORIGINAL ARTICLES: LUNG CANCER Miliary metastases are associated with epidermal growth factor receptor mutations in non-small cell lung cancer: a population-based study Fred Hsu, Alan Nichol , Ted Toriumi & Alex De Caluwe Pages: 1175-1180 | DOI: 10.1080/0284186X.2017.1328128 Correlation analysis of [18F]fluorodeoxyglucose and [18F]fluoroazomycin arabinoside uptake distributions in lung tumours during radiation therapy Dario Di Perri , John A. Lee, Anne Bol, François-Xavier Hanin, Guillaume Janssens, Daniel Labar, Annie Robert, Edmond Sterpin & Xavier Geets Pages: 1181-1188 | DOI: 10.1080/0284186X.2017.1329594 Accuracy of the dose-shift approximation in estimating the delivered dose in SBRT of lung tumors considering setup errors and breathing motions Kristin Karlsson, Ingmar Lax, Elias Lindbäck & Gavin Poludniowski Pages: 1189-1196 | DOI: 10.1080/0284186X.2017.1310395 ORIGINAL ARTICLES: HEAD-AND-NECK CANCER Parotid gland mean dose as a xerostomia predictor in low-dose domains Hubert Szymon Gabryś , Florian Buettner , Florian Sterzing, Henrik Hauswald & Mark Bangert Pages: 1197-1203 | DOI: 10.1080/0284186X.2017.1324209 Increasing incidence and survival in oral cancer: a nationwide Danish study from 1980 to 2014 Kirstine Kim Schmidt Karnov , Christian Grønhøj, David Hebbelstrup Jensen, Irene Wessel, Birgitte Wittenborg Charabi, Lena Specht, Andreas Kjaer & Christian von Buchwald Pages: 1204-1209 | DOI: 10.1080/0284186X.2017.1307516 ORIGINAL ARTICLES: SUPPORTIVE CARE Admittance to specialized palliative care (SPC) of patients with an assessed need: a study from the Danish palliative care database (DPD) Mathilde Adsersen, Lau Caspar Thygesen, Mette Asbjoern Neergaard, Anders Bonde Jensen, Per Sjøgren, Anette Damkier & Mogens Groenvold Pages: 1210-1217 | DOI: 10.1080/0284186X.2017.1332425 Adverse events in hospitalised cancer patients: a comparison to a general hospital population | Ellinor Christin Haukland, Christian von Plessen, Carsten Nieder & Barthold Vonen Pages: 1218-1223 | DOI: 10.1080/0284186X.2017.1309063 ORIGINAL ARTICLES: GASTROINTESTINAL CANCER Significance of baseline FDG-PET/CT scan as a method of staging regional lymph nodes in patients with operable distal oesophageal or gastroesophageal junction adenocarcinoma George Papaxoinis, Jamie M. J. Weaver, Leila Khoja, Ana Patrao, Sofia Stamatopoulou, Alia Alchawaf, Vikki Owen-Holt, Theodora Germetaki, Zoe Kordatou & Wasat Mansoor Pages: 1224-1232 | DOI: 10.1080/0284186X.2017.1328127 LETTERS TO THE EDITOR Fatal heart failure in a young adult female sarcoma patient treated with pazopanib | Vicky L. M. N. Soomers, Ingrid M. E. Desar, Nielka P. van Erp, Jeroen Verwiel, Suzanne E. J. Kaal & Winette T. A. van der Graaf Pages: 1233-1234 | DOI: 10.1080/0284186X.2017.1296582 Combined modality therapy improves overall survival for angiosarcoma Colette J. Shen, Aaron S. Parzuchowski, Megan N. Kummerlowe, Carol D. Morris, Christian F. Meyer, Mehran Habibi, Deborah A. Frassica, Adam S. Levin, Katherine A. Thornton & Stephanie A. Terezakis Pages: 1235-1238 | DOI: 10.1080/0284186X.2017.1306104 Boosting axitinib exposure with a CYP3A4 inhibitor, making axitinib treatment personal Floor J. E. Lubberman, Nielka P. van Erp, Rob ter Heine & Carla M. L. van Herpen Pages: 1238-1240 | DOI: 10.1080/0284186X.2017.1311024 Radiation physiology – evidence for a higher biological effect of 24 Gy in four fractions as compared to three Gunnar Steineck , Cecilia Bull, Marie Kalm, Fei Sjöberg, Eleftheria Alevronta, Dilip Kumar Malipatlolla, Karin Bergmark, Bengt Jeppsson, Ulrica Wilderäng & Thomas Björk-Eriksson Pages: 1240-1243 | DOI: 10.1080/0284186X.2017.1309062 Mid-treatment magnetic resonance imaging in pediatric intracranial low-grade gliomas treated with proton beam therapy Radhika Sreeraman Kumar, Ronny L. Rotondo, Julie A. Bradley, Tamara Vern-Gross, Soon Huh & Daniel J. Indelicato Pages: 1243-1247 | DOI: 10.1080/0284186X.2017.1306105 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : International Journal of Performance Arts and Digital Media, Volume 13, Issue 2, October 2017 is now available online on Taylor & Francis Online

The online platform for Taylor & Francis Online content International Journal of Performance Arts and Digital Media, Volume 13, Issue 2, October 2017 is now available online on Taylor & Francis Online. "Bodily Extensions and Performance" Guest Edited by Sita Popat and Sarah Whatley This new issue contains the following articles: Editorial Bodily extensions and performance Sita Popat , Sarah Whatley, Rory O'Connor, Abbe Brown & Shawn Harmon Pages: 101-104 | DOI: 10.1080/14794713.2017.1358525 Articles Beyond the cyborg: performance, attunement and autonomous computation Marco Donnarumma Pages: 105-119 | DOI: 10.1080/14794713.2017.1338828 Postphenomenological performance: bodily extensions in interactive art Daniel Paul O'Brien Pages: 120-136 | DOI: 10.1080/14794713.2017.1351658 The composition of posthuman bodies Samuel Wilson Pages: 137-152 | DOI: 10.1080/14794713.2017.1338854 Breaching bodily boundaries: posthuman (dis)embodiment and ecstatic speech in lip-synch performances by boychild | Leila Riszko Pages: 153-169 | DOI: 10.1080/14794713.2017.1348094 'Savage Beauties'. Alexander McQueen's performance of posthuman bodies Justyna Stępień Pages: 170-182 | DOI: 10.1080/14794713.2017.1345584 Choreography for One, Two, and Three Legs (A phenomenological meditation in movements) Vivian Sobchack Pages: 183-198 | DOI: 10.1080/14794713.2017.1345583 Book review The prosthetic pedagogy of art: embodied research and practice Joanne Scott Pages: 199-200 | DOI: 10.1080/14794713.2017.1355724 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Genetics of Cushing's disease

Summary

Cushing's disease (CD) is a rare disabling condition caused by ACTH-secreting adenomas of the pituitary. The majority of corticotropic adenomas are monoclonal and occur sporadically. Only rarely does CD arise in the context of genetic familial syndromes. Targeted sequencing of oncogenes and tumour-suppressor genes commonly mutated in other tumours did not identify recurrent mutations. In contrast, next generation sequencing allowed us recently to clarify the genetic basis of CD: We identified somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene in a significant portion of corticotropinomas. These mutations represent a novel and unique mechanism leading to ACTH excess. Inhibition of USP8 or its downstream signalling pathways could represent a new therapeutic approach for the management of CD. In this review we will focus on this new evidence and its implication for clinical care of affected patients.

This article is protected by copyright. All rights reserved.

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The association between subclinical thyroid dysfunction and dementia: the Health, Aging and Body Composition (Health ABC) Study

Abstract

Objective

Data on the association between subclinical thyroid dysfunction and dementia are limited and conflicting. We aimed to determine whether subclinical thyroid dysfunction was associated with dementia and cognitive decline.

Design

Population-based prospective cohort study.

Patients

Adults aged 70-79 years with measured thyroid function, but no dementia at baseline, and Modified Mini-Mental State (3MS) at baseline and follow-up.

Measurements

Primary outcome was incident adjudicated dementia, based on 3MS, hospital records, and dementia drugs. Secondary outcome was change in 3MS. Models were adjusted for age, sex, race, education, and baseline 3MS, and then further for cardiovascular risk factors.

Results

Among 2558 adults, 85% were euthyroid (TSH 0.45-4.49mIU/L), 2% had subclinical hyperthyroidism with mildly decreased TSH (TSH 0.10- 0.44mIU/L), 1% subclinical hyperthyroidism with suppressed TSH (TSH<0.10mIU/L with normal free thyroxine [FT4]) and 12% subclinical hypothyroidism (TSH 4.50-19.99mIU/L with normal FT4). Over 9 years, 22% developed dementia. Compared to euthyroidism, risk of dementia was higher in participants with subclinical hyperthyroidisim with suppressed TSH (HR 2.38, 95%CI=1.13;5.04), while we found no significant association in those with mildly decreased TSH (HR 0.79, 95%CI=0.45;1.38) or with subclinical hypothyroidism (HR 0.91, 95%CI=0.70;1.19). Participants with subclinical hyperthyroidism with suppressed TSH had a larger decline in 3MS (-3.89, 95%CI=-7.62;-0.15).

Conclusions

Among older adults, subclinical hyperthyroidism with a TSH<0.10mIU/L was associated with a higher risk of dementia and a larger cognitive decline, while subclinical hyperthyroidism with mildly decreased TSH or subclinical hypothyroidism were not.

This article is protected by copyright. All rights reserved.

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Toxicological effects of chemical constituents from Piper against the environmental burden Aedes aegypti Liston and their impact on non-target toxicity evaluation against biomonitoring aquatic insects

Abstract

Dengue is the most rapidly spreading mosquito-borne viral disease in the world. The mosquito, Aedes aegypti, also spreads Yellow fever, Chikungunya, and Zika virus. As the primary vector for dengue, Ae. aegypti now occurs in over 20 countries and is a serious concern with reports of increasing insecticide resistance. Developing new treatments to manage mosquitoes are needed. Formulation of crude volatile oil from Piper betle leaves (Pb-CVO) was evaluated as a potential treatment which showed larvicidal, ovipositional, and repellency effects. Gut-histology and enzyme profiles were analyzed post treatment under in-vitro conditions. The Pb-CVO from leaves of field collected plants was obtained by steam distillation and separated through rotary evaporation. The Pb-CVO were evaluated for chemical constituents through GC-MS analyses revealed 20 vital compounds. The peak area was establish to be superior in Eudesm-7(11)-en-4-ol (14.95%). Pb-CVO were determined and tested as four different concentrations (0.25, 0.5, 1.0, and 1.5 mg/L) of Pb-CVO towards Ae. aegypti. The larvicidal effects exhibited dose dependent mortality being greatest at 1.5 mg Pb-CVO/10 g leaves. The LC₅₀ occurred at 0.63 mg Pb-CVO/L. Larva of Ae. aegypti exposed to Pb-CVO showed significantly reduced digestive enzyme actions of α- and β-carboxylesterases. In contrast, GST and CYP450 enzyme levels increased significantly as concentration increased. Correspondingly, oviposition deterrence index and egg hatch of Ae. aegypti exposed to sub-lethal doses of Pb-CVO demonstrated a strong effect suitable for population suppression. Repellency at 0.6 mg Pb-CVO applied as oil had a protection time of 15–210 min. Mid-gut histological of Ae. aegypti larvae showed severe damage when treated with 0.6 mg of Pb-CVO treatment compared to the control. Non-toxic effects against aquatic beneficial insects, such as Anisops bouvieri and Toxorhynchites splendens, were observed at the highest concentrations, exposed for 3 h. These results suggest that the Pb-CVO may contain effective constituents suitable for development of new vector control agents against Ae. aegypti.

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Neural Noise Hypothesis of Developmental Dyslexia

Publication date: Available online 28 August 2017
Source:Trends in Cognitive Sciences
Author(s): Roeland Hancock, Kenneth R. Pugh, Fumiko Hoeft




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Enhanced adsorption of hexavalent chromium by a biochar derived from ramie biomass ( Boehmeria nivea (L.) Gaud.) modified with β-cyclodextrin/poly(L-glutamic acid)

Abstract

This paper explored biochar modification to enhance biochar's ability to adsorb hexavalent chromium from aqueous solution. The ramie stem biomass was pyrolyzed and then treated by β-cyclodextrin/poly(L-glutamic acid) which contained plentiful functional groups. The pristine and modified biochar were characterized by FTIR, X-ray photoelectron spectroscopy, specific surface area, and zeta potential measurement. Results indicated that the β-cyclodextrin/poly(L-glutamic acid) was successfully bound to the biochar surface. Batch experiments were conducted to investigate the kinetics, isotherm, thermodynamics, and adsorption/desorption of Cr(VI). Adsorption capacities of CGA-biochar were significantly higher than that of the untreated biochar, and its maximum adsorption capacity could reach up to 197.21 mg/g at pH 2.0. Results also illustrated that sorption performance depended on initial solution pH; in addition, acidic condition was beneficial to the Cr(VI) uptake. Furthermore, the Cr(VI) uptake was significantly affected by the ion strength and cation species. This study demonstrated that CGA-biochar could be a potential adsorbent for Cr(VI) pollution control.

http://ift.tt/2wZ9sff

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[PDF] Διερεύνηση της πολυφαρμακίας στα μέλη των ΚΑΠΗ της Πάτρας και των παραγόντων που την επηρεάζουν

Μ Ξυντάρα - 2017

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ΜΕΤΑΠΤΥΧΙΑΚΗ ΔΙΠΛΩΜΑΤΙΚΗ ΕΡΓΑΣΙΑ «Διερεύνηση της πολυφαρμακίας στα μέλη των ΚΑΠΗ
της Πάτρας και των παραγόντων που την επηρεάζουν» Μαρίνα Ξυντάρα, ...

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