Author: Zannad, Faiez MD, PhD; Rossignol, Patrick MD, PhD
Page: 1769-1771
http://ift.tt/2pYBUKA
Δευτέρα 8 Μαΐου 2017
Public Reporting II: State of the Art-Current Public Reporting in Cardiovascular Medicine.
Author: Weintraub, William S. MD; Garratt, Kirk N. MD
Page: 1772-1774
http://ift.tt/2q0pksn
Sources of Sodium in US Adults From 3 Geographic Regions.
Author: Harnack, Lisa J. DrPH; Cogswell, Mary E. DrPH; Shikany, James M. PhD; Gardner, Christopher D. PhD; Gillespie, Cathleen MS; Loria, Catherine M. PhD; Zhou, Xia MS; Yuan, Keming MS; Steffen, Lyn M. PhD
Page: 1775-1783
http://ift.tt/2pYufvW
Sources of Dietary Sodium: Implications for Patients, Physicians, and Policy.
Author: Appel, Lawrence J. MD, MPH; Foti, Kathryn MPH
Page: 1784-1787
http://ift.tt/2q0K96O
Effect of Aggressive Blood Pressure Control on the Recurrence of Atrial Fibrillation After Catheter Ablation: A Randomized, Open-Label Clinical Trial (SMAC-AF [Substrate Modification With Aggressive Blood Pressure Control]).
Author: Parkash, Ratika MD, MS; Wells, George A. PhD; Sapp, John L. MD; Healey, Jeffrey S. MD; Tardif, Jean-Claude MD; Greiss, Isabelle MD; Rivard, Lena MD, MSc; Roux, Jean-Francois MD; Gula, Lorne MD; Nault, Isabelle MD; Novak, Paul MD; Birnie, David MD; Ha, Andrew MD; Wilton, Stephen B. MD, MSc; Mangat, Iqwal MD; Gray, Christopher MD; Gardner, Martin MD; Tang, Anthony S.L. MD
Page: 1788-1798
http://ift.tt/2pYqOoX
Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration.
Author: Freedman, Ben MBBS, PhD *; Camm, John MD *; Calkins, Hugh MD *; Healey, Jeffrey S. MD, MSc *; Rosenqvist, Marten MD, PhD *; Wang, Jiguang MD, PhD *; Albert, Christine M. MD, MPH; Anderson, Craig S. PhD; Antoniou, Sotiris BPharm(Hons), MSc; Benjamin, Emelia J. MD, ScM; Boriani, Giuseppe MD, PhD; Brachmann, Johannes MD, PhD; Brandes, Axel MD, DMSc; Chao, Tze-Fan MD, PhD; Conen, David MD, MPH; Engdahl, Johan MD, PhD; Fauchier, Laurent MD, PhD; Fitzmaurice, David A. MD; Friberg, Leif MD, PhD; Gersh, Bernard J. MB, ChB, DPhil; Gladstone, David J. MD, PhD; Glotzer, Taya V. MD; Gwynne, Kylie MA; Hankey, Graeme J. MD; Harbison, Joseph MD; Hillis, Graham S. MBChB, PhD; Hills, Mellanie T. BSc; Kamel, Hooman MD; Kirchhof, Paulus MD; Kowey, Peter R. MD; Krieger, Derk MD, PhD; Lee, Vivian W. Y. BSc, PharmD; Levin, Lars-Ake PhD; Lip, Gregory Y. H. MD; Lobban, Trudie; Lowres, Nicole PhD; Mairesse, Georges H. MD; Martinez, Carlos MD, MSc; Neubeck, Lis BA(Hons), PhD; Orchard, Jessica BEc/LLB, MPH; Piccini, Jonathan P. MD, MHS; Poppe, Katrina PhD; Potpara, Tatjana S. MD, PhD; Puererfellner, Helmut MD; Rienstra, Michiel MD, PhD; Sandhu, Roopinder K. MD, MPH; Schnabel, Renate B. MD, MSc *; Siu, Chung-Wah MD; Steinhubl, Steven MD; Svendsen, Jesper H. MD, DMSc; Svennberg, Emma MD, PhD; Themistoclakis, Sakis MD; Tieleman, Robert G. MD, PhD; Turakhia, Mintu P. MD, MAS; Tveit, Arnljot MD, PhD; Uittenbogaart, Steven B. MD, MSc; Van Gelder, Isabelle C. MD, PhD; Verma, Atul MD; Wachter, Rolf MD; Yan, Bryan P. MBBS.
Page: 1851-1867
http://ift.tt/2q0HESf
Transcatheter Treatment of Severe Tricuspid Regurgitation With the Edge-to-Edge MitraClip Technique.
Author: Nickenig, Georg MD; Kowalski, Marek MD; Hausleiter, Jorg MD; Braun, Daniel MD; Schofer, Joachim MD; Yzeiraj, Ermela MD; Rudolph, Volker MD; Friedrichs, Kai MD; Maisano, Francesco MD; Taramasso, Maurizio MD; Fam, Neil MD; Bianchi, Giovanni MD; Bedogni, Francesco MD; Denti, Paolo MD; Alfieri, Ottavio MD; Latib, Azeem MD; Colombo, Antonio MD; Hammerstingl, Christoph MD; Schueler, Robert MD
Page: 1802-1814
http://ift.tt/2pYGPLx
Blood Pressure Control in Atrial Fibrillation: One of Many Critical Components in Risk Factor Modification.
Author: Lau, Dennis H. MBBS, PhD; Hendriks, Jeroen PhD; Kalman, Jonathan M. MBBS, PhD; Sanders, Prashanthan MBBS, PhD
Page: 1799-1801
http://ift.tt/2q0Jtyj
Percutaneous Therapy for Tricuspid Regurgitation: A New Frontier for Interventional Cardiology.
Author: Kapadia, Samir MD; Krishnaswamy, Amar MD; Tuzcu, E. Murat MD
Page: 1815-1818
http://ift.tt/2q0K8Qi
Pooled Safety Analysis of Evolocumab in Over 6000 Patients From Double-Blind and Open-Label Extension Studies.
Author: Toth, Peter P. MD, PhD; Descamps, Olivier MD, PhD; Genest, Jacques MD; Sattar, Naveed MD, PhD; Preiss, David MD, PhD; Dent, Ricardo MD; Djedjos, Constantine MD; Wu, Yuna PhD; Geller, Michelle MD; Uhart, Magdalena MD; Somaratne, Ransi MD; Wasserman, Scott M. MD; for the PROFICIO Investigators
Page: 1819-1831
http://ift.tt/2pYp1Ae
Defined Engineered Human Myocardium With Advanced Maturation for Applications in Heart Failure Modeling and Repair.
Author: Tiburcy, Malte MD; Hudson, James E. PhD; Balfanz, Paul; Schlick, Susanne MS; Meyer, Tim PhD; Chang Liao, Mei-Ling PhD; Levent, Elif PhD; Raad, Farah PhD; Zeidler, Sebastian PhD; Wingender, Edgar PhD; Riegler, Johannes PhD; Wang, Mouer MD; Gold, Joseph D. PhD; Kehat, Izhak MD, PhD; Wettwer, Erich PhD; Ravens, Ursula MD, PhD; Dierickx, Pieterjan PhD; van Laake, Linda W. MD, PhD; Goumans, Marie Jose PhD; Khadjeh, Sara PhD; Toischer, Karl MD; Hasenfuss, Gerd MD; Couture, Larry A. PhD; Unger, Andreas PhD; Linke, Wolfgang A. PhD; Araki, Toshiyuki PhD; Neel, Benjamin MD, PhD; Keller, Gordon PhD; Gepstein, Lior MD, PhD; Wu, Joseph C. MD, PhD; Zimmermann, Wolfram-Hubertus MD
Page: 1832-1847
http://ift.tt/2q0BEcf
One Stride Forward: Maturation and Scalable Production of Engineered Human Myocardium.
Author: Yang, Xiulan PhD; Murry, Charles E. MD, PhD
Page: 1848-1850
http://ift.tt/2pYxMKR
Added Sugars and Cardiovascular Disease Risk in Children: A Scientific Statement From the American Heart Association.
Author: Vos, Miriam B. MD, MSPH, FAHA; Chair; Kaar, Jill L. PhD; Welsh, Jean A. PhD, MPH, RN; Van Horn, Linda V. PhD, RD, FAHA; Feig, Daniel I. MD, PhD; Anderson, Cheryl A.M. PhD, MPH, MS, FAHA; Patel, Mahesh J. MD; Cruz Munos, Jessica MD; Krebs, Nancy F. MD, MS; Xanthakos, Stavra A. MD, MS; Johnson, Rachel K. PhD, MPH, RD, FAHA; On behalf of the American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; Council on Functional Genomics and Translational Biology; and Council on Hypertension
Page: e1017-e1034
http://ift.tt/2pYDs7w
Highlights of the American College of Cardiology Annual Scientific Sessions 2017.
Author: Kuvin, Jeffrey T. MD; Kates, Andrew M. MD
Page: 1868-1869
http://ift.tt/2q0N6EG
Wide QRS Complex Tachycardia: What Is the Diagnosis?.
Author: Wang, Gaopin; Liu, Renguang; Chang, Qinghua MD
Page: 1870-1872
http://ift.tt/2q0OaYU
Impact of Structural Cerebral Damage in Adults With Tetralogy of Fallot.
Author: Sluman, Maayke A. MD; Richard, Edo MD, PhD; Bouma, Berto J. MD, PhD; van Dalen, Jan Willem MSc; van Wanrooij, Lennard L. MSc; Groenink, Maarten MD, PhD; Caan, Matthan W. A. PhD; Nederveen, Aart J. PhD; Mutsaerts, Henk-Jan M. M. MD, PhD; Majoie, Charles B. L. M. MD, PhD; Schmand, Ben A. PhD; Mulder, Barbara J. M. MD, PhD
Page: 1873-1875
http://ift.tt/2pYNc1r
Letter by Damen et al Regarding Article, "A Critical Appraisal of Aspirin in Secondary Prevention: Is Less More?".
Author: Damen, Sander A. J. MD; Brouwer, Marc A. MD, PhD; Verheugt, Freek W. A. MD, PhD
Page: e1035-e1036
http://ift.tt/2q0YCzJ
Response by Valgimigli and Gargiulo to Letter Regarding Article, "A Critical Appraisal of Aspirin in Secondary Prevention: Is Less More?".
Author: Valgimigli, Marco MD, PhD; Gargiulo, Giuseppe MD
Page: e1037-e1038
http://ift.tt/2pYqIxB
Letter by Puri et al Regarding Article, "Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control".
Author: Puri, Raman DM; Puri, Sonam MD; Rajani, Anil MD
Page: e1039-e1040
http://ift.tt/2q0J1QJ
Correction to: Percutaneous Therapy for Tricuspid Regurgitation: A New Frontier for Interventional Cardiology.
Author:
Page: e1041
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β Cell Renewal versus Differentiation: Slow and Steady Wins the Race
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Ondine Cleaver
Pancreatic endocrine progenitor cells proliferate and transiently express the bHLH transcription factor Ngn3. In recent issues of Developmental Cell, Azzarelli et al. (2017) and Krentz et al. (2017) demonstrate how CDK phosphorylation of Ngn3 governs the switch between their renewal and differentiation. Lengthening the cell cycle allows Ngn3 accumulation, outpacing phosphorylation-induced degradation.
Teaser
Pancreatic endocrine progenitor cells proliferate and transiently express the bHLH transcription factor Ngn3. In recent issues of Developmental Cell, Azzarelli et al. (2017) and Krentz et al. (2017) demonstrate how CDK phosphorylation of Ngn3 governs the switch between their renewal and differentiation. Lengthening the cell cycle allows Ngn3 accumulation, outpacing phosphorylation-induced degradation.http://ift.tt/2q12BMU
A Geometric Model of Stripe Refinement
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Eric D. Siggia
Organizing data about patterning and morphogenesis into a coherent framework remains a challenge in developmental biology. Reporting in Science, Corson et al. (2017) apply innovative analysis to an old problem of bristle patterns in Drosophila, reducing the nonlinear interactions among tens of cells to a succinct model with quantitative predictions.
Teaser
Organizing data about patterning and morphogenesis into a coherent framework remains a challenge in developmental biology. Reporting in Science, Corson et al. (2017) apply innovative analysis to an old problem of bristle patterns in Drosophila, reducing the nonlinear interactions among tens of cells to a succinct model with quantitative predictions.http://ift.tt/2pYfoS8
The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Rhett A. Kovall, Brian Gebelein, David Sprinzak, Raphael Kopan
The Notch signaling pathway relies on a proteolytic cascade to release its transcriptionally active intracellular domain, on force to unfold a protective domain and permit proteolysis, on extracellular domain glycosylation to tune the forces exerted by endocytosed ligands, and on a motley crew of nuclear proteins, chromatin modifiers, ubiquitin ligases, and a few kinases to regulate activity and half-life. Herein we provide a review of recent molecular insights into how Notch signals are triggered and how cell shape affects these events, and we use the new insights to illuminate a few perplexing observations.
Teaser
In this review, Kovall et al. describe structure-based insights into Notch receptor/ligand interactions, the proteins involved in receptor modifications and cleavage, details on what forces are required to activate Notch, how cell shape might affect this process, and how the active NICD molecule mediates changes in gene expression.http://ift.tt/2q0Igaq
Gastric Acid Secretion from Parietal Cells Is Mediated by a Ca2+ Efflux Channel in the Tubulovesicle
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Nirakar Sahoo, Mingxue Gu, Xiaoli Zhang, Neel Raval, Junsheng Yang, Michael Bekier, Raul Calvo, Samarjit Patnaik, Wuyang Wang, Greyson King, Mohammad Samie, Qiong Gao, Sasmita Sahoo, Sinju Sundaresan, Theresa M. Keeley, Yanzhuang Wang, Juan Marugan, Marc Ferrer, Linda C. Samuelson, Juanita L. Merchant, Haoxing Xu
Gastric acid secretion by parietal cells requires trafficking and exocytosis of H/K-ATPase-rich tubulovesicles (TVs) toward apical membranes in response to histamine stimulation via cyclic AMP elevation. Here, we found that TRPML1 (ML1), a protein that is mutated in type IV mucolipidosis (ML-IV), is a tubulovesicular channel essential for TV exocytosis and acid secretion. Whereas ML-IV patients are reportedly achlorhydric, transgenic overexpression of ML1 in mouse parietal cells induced constitutive acid secretion. Gastric acid secretion was blocked and stimulated by ML1 inhibitors and agonists, respectively. Organelle-targeted Ca2+ imaging and direct patch-clamping of apical vacuolar membranes revealed that ML1 mediates a PKA-activated conductance on TV membranes that is required for histamine-induced Ca2+ release from TV stores. Hence, we demonstrated that ML1, acting as a Ca2+ channel in TVs, links transmitter-initiated cyclic nucleotide signaling with Ca2+-dependent TV exocytosis in parietal cells, providing a regulatory mechanism that could be targeted to manage acid-related gastric diseases.
Graphical abstract
Teaser
Acid secretion from the parietal cells of the stomach is essential for food digestion. Sahoo et al. identified TRPML1 as a histamine-activated Ca2+ channel in the tubulovesicles required for gastric acid secretion. Synthetic agonists and inhibitors of TRPML1 may be developed to control acid secretion and treat acid-related gastric diseases.http://ift.tt/2pYycRa
More Cytoplasm, More Problems
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Predrag Jevtić, Daniel L. Levy
In this issue of Developmental Cell, Kyogoku and Kitajima (2017) investigate the effect of cytoplasmic volume on the fidelity of chromosome segregation during meiosis in mouse oocytes. The authors find that large cytoplasmic volume affects spindle pole morphology, chromosome alignment, and stringency of checkpoint signaling, resulting in error-prone chromosome segregation.
Teaser
In this issue of Developmental Cell, Kyogoku and Kitajima (2017) investigate the effect of cytoplasmic volume on the fidelity of chromosome segregation during meiosis in mouse oocytes. The authors find that large cytoplasmic volume affects spindle pole morphology, chromosome alignment, and stringency of checkpoint signaling, resulting in error-prone chromosome segregation.http://ift.tt/2pYl3rk
Large Cytoplasm Is Linked to the Error-Prone Nature of Oocytes
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Hirohisa Kyogoku, Tomoya S. Kitajima
Chromosome segregation during meiosis in oocytes is error prone. The uniquely large cytoplasmic size of oocytes, which provides support for embryogenesis after fertilization, might be a predisposing factor for meiotic errors. However, this hypothesis remains unproven. Here, we show that cytoplasmic size affects the functionality of the acentrosomal spindle. Artificially decreasing the cytoplasmic size in mouse oocytes allows the acentrosomal spindle poles to have a better-focused distribution of microtubule-organizing centers and to biorient chromosomes more efficiently, whereas enlargement of the cytoplasmic size has the opposite effects. Moreover, we found that the cytoplasmic size-dependent dilution of nuclear factors, including anaphase inhibitors that are preformed at the nuclear membrane, limits the spindle's capacity to prevent anaphase entry with misaligned chromosomes. The present study defines a large cytoplasmic volume as a cell-intrinsic feature linked to the error-prone nature of oocytes. This may represent a trade-off between meiotic fidelity and post-fertilization developmental competence.
Graphical abstract
Teaser
Kyogoku and Kitajima show that cytoplasmic size affects the functionality of the acentrosomal spindle and the stringency of the spindle checkpoint in mouse oocytes, thus providing evidence that the large cytoplasmic size of oocytes is linked to error-prone chromosome segregation during female meiosis, which is a leading cause of aneuploidy.http://ift.tt/2q0DXMf
The PomXYZ Proteins Self-Organize on the Bacterial Nucleoid to Stimulate Cell Division
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Dominik Schumacher, Silke Bergeler, Andrea Harms, Janet Vonck, Sabrina Huneke-Vogt, Erwin Frey, Lotte Søgaard-Andersen
Cell division site positioning is precisely regulated to generate correctly sized and shaped daughters. We uncover the strategy used by the social bacterium Myxococcus xanthus to position the FtsZ cytokinetic ring at midcell. PomX, PomY, and the nucleoid-binding ParA/MinD ATPase PomZ self-assemble forming a large nucleoid-associated complex that localizes at the division site before FtsZ to directly guide and stimulate division. PomXYZ localization is generated through self-organized biased random motion on the nucleoid toward midcell and constrained motion at midcell. Experiments and theory show that PomXYZ motion is produced by diffusive PomZ fluxes on the nucleoid into the complex. Flux differences scale with the intracellular asymmetry of the complex and are converted into a local PomZ concentration gradient across the complex with translocation toward the higher PomZ concentration. At midcell, fluxes equalize resulting in constrained motion. Flux-based mechanisms may represent a general paradigm for positioning of macromolecular structures in bacteria.
Teaser
Schumacher et al. find that the PomXYZ complex self-organizes on the bacterial nucleoid and promotes positioning of the cytokinetic ring. Diffusive fluxes of PomZ into the complex scale with intracellular asymmetry and are converted into a local PomZ concentration gradient that promotes biased motion toward and constrained motion at midcell.http://ift.tt/2q0l5gr
RhoD Inhibits RhoC-ROCK-Dependent Cell Contraction via PAK6
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Charlotte H. Durkin, Flavia Leite, João V. Cordeiro, Yutaka Handa, Yoshiki Arakawa, Ferran Valderrama, Michael Way
RhoA-mediated regulation of myosin-II activity in the actin cortex controls the ability of cells to contract and bleb during a variety of cellular processes, including cell migration and division. Cell contraction and blebbing also frequently occur as part of the cytopathic effect seen during many different viral infections. We now demonstrate that the vaccinia virus protein F11, which localizes to the plasma membrane, is required for ROCK-mediated cell contraction from 2 hr post infection. Curiously, F11-induced cell contraction is dependent on RhoC and not RhoA signaling to ROCK. Moreover, RhoC-driven cell contraction depends on the upstream inhibition of RhoD signaling by F11. This inhibition prevents RhoD from regulating its downstream effector Pak6, alleviating the suppression of RhoC by the kinase. Our observations with vaccinia have now demonstrated that RhoD recruits Pak6 to the plasma membrane to antagonize RhoC signaling during cell contraction and blebbing.
Graphical abstract
Teaser
Many different viral infections induce cell contraction and blebbing. Durkin, Leite, et al. show that during vaccinia infection, RhoC and not RhoA regulates this ROCK-mediated cytopathic effect of cell contraction. They delineate a pathway for RhoC regulation, in which the viral protein F11 blocks RhoC antagonism by RhoD-recruited Pak6.http://ift.tt/2pYyQOS
Abl Regulates Planar Polarized Junctional Dynamics through β-Catenin Tyrosine Phosphorylation
Publication date: 8 May 2017
Source:Developmental Cell, Volume 41, Issue 3
Author(s): Masako Tamada, Dene L. Farrell, Jennifer A. Zallen
http://ift.tt/2pYpCC5
The involvement of brain-derived neurotrophic factor in 3,4-methylenedioxymethamphetamine-induced place preference and behavioral sensitization
Source:Behavioural Brain Research, Volume 329
Author(s): Akihiro Mouri, Yukihiro Noda, Minae Niwa, Yurie Matsumoto, Takayoshi Mamiya, Atsumi Nitta, Kiyofumi Yamada, Shoei Furukawa, Tatsunori Iwamura, Toshitaka Nabeshima
3,4-Methylenedioxymethamphetamine (MDMA) is known to induce dependence and psychosis in humans. Brain-derived neurotrophic factor (BDNF) is involved in the synaptic plasticity and neurotrophy in midbrain dopaminergic neurons. This study aimed to investigate the role of BDNF in MDMA-induced dependence and psychosis. A single dose of MDMA (10mg/kg) induced BDNF mRNA expression in the prefrontal cortex, nucleus accumbens, and amygdala, but not in the striatum or the hippocampus. However, repeated MDMA administration for 7 days induced BDNF mRNA expression in the striatum and hippocampus. Both precursor and mature BDNF protein expression increased in the nucleus accumbens, mainly in the neurons. Additionally, rapidly increased extracellular serotonin levels and gradually and modestly increased extracellular dopamine levels were noted within the nucleus accumbens of mice after repeated MDMA administration. Dopamine receptor antagonists attenuated the effect of repeated MDMA administration on BDNF mRNA expression in the nucleus accumbens. To examine the role of endogenous BDNF in the behavioral and neurochemical effects of MDMA, we used mice with heterozygous deletions of the BDNF gene. MDMA-induced place preference, behavioral sensitization, and an increase in the levels of extracellular serotonin and dopamine within the nucleus accumbens, were attenuated in BDNF heterozygous knockout mice. These results suggest that BDNF is implicated in MDMA-induced dependence and psychosis by activating the midbrain serotonergic and dopaminergic neurons.
http://ift.tt/2pexMqC
Antidepressant-like effect of valproic acid—Possible involvement of PI3K/Akt/mTOR pathway
Source:Behavioural Brain Research, Volume 329
Author(s): Isabel Vieira de Assis Lima, Ana Flávia Almeida-Santos, Talita Hélen Ferreira-Vieira, Daniele Cristina Aguiar, Fabíola Mara Ribeiro, Alline Cristina Campos, Antônio Carlos Pinheiro de Oliveira
RationaleFew studies suggest that antidepressants exert their effects by activating some signaling pathways, including the phosphatidylinositol 3-kinase (PI3K). Moreover, valproic acid (VPA) activates the PI3K pathway. Thus, here we investigated the antidepressant-like effect of VPA and if its effect is related to PI3K/Akt/mTOR activation.MethodsC57Bl/6 (WT) and PI3Kγ−/− mice received VPA injections (30, 100 or 300mg/kg, i.p.) and 30min after they were submitted to the forced swimming (FS), tail suspension (TS) and open field (OF) tests. Another group was pretreated with rapamycin (5mg/kg, i.p.) 150min before VPA administration. Akt phosphorylation levels were measured by Western blotting.ResultsIn WT mice, VPA (30mg/kg) reduced the immobility time in both FS and TS tests. However, VPA (300mg/kg) increased the immobility time in FS test. All doses of VPA did not alter locomotor activity. In PI3Kγ−/− mice, none of the doses revealed antidepressant-like effect. However, in the OF test, the lower dose of VPA increased the travelled distance in comparison with vehicle group. An increase in Akt phosphorylation levels was observed in WT, but not in PI3Kγ−/− mice. Finally, the pretreatment of WT mice with rapamycin abolished the antidepressant-like effect of VPA (30mg/kg) in FS test.ConclusionThese data suggest that the antidepressant-like effects of VPA might depend on PI3K and mTOR activation. Thus, more studies are necessary to investigate the mechanisms involved in the antidepressant-like effect induced by VPA in order to investigate novel therapeutic targets for the treatment of depression.
http://ift.tt/2peCzIN
Semantic memory deficits are associated with pica in individuals with acquired brain injury
Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Michitaka Funayama, Taro Muramatsu, Akihiro Koreki, Motoichiro Kato, Masaru Mimura, Yoshitaka Nakagawa
Although pica is one of the most prominent signs in individuals with severe cognitive impairment, the mechanisms and neural basis for pica have not been well elucidated. To address this issue, patients with acquired brain injury who showed pica and hyperorality were investigated. Eleven patients with pica, i.e., individuals who eat non-food items, and eight patients with hyperorality but who never eat non-food items were recruited. The cognitive and behavioral assessments and neural substrates of the two groups were compared. For basic cognitive and behavioral functions, two kinds of mental state examination—the mini-mental state examination and the new clinical scale for rating of mental states of the elderly—were administered. For pica-related behavioral features, frontal release signs, semantic memory deficits, and changes in eating behaviors were compared. Compared with the hyperorality group, the pica group had more severe semantic memory deficits and fewer frontal release signs, whereas there was no significant difference in changes in eating behaviors. Individuals in the pica group always had a lesion in the posterior part of the middle temporal gyrus. These findings suggest that semantic memory deficits following temporal lobe damage are associated with pica.
http://ift.tt/2qUhVdj
A new construct of antibody-drug conjugates for treatment of B-cell non-Hodgkin's lymphomas
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Libin Zhang, Yixin Fang, Jindřich Kopeček, Jiyuan Yang
The aim of this study was to develop a new class of antibody-drug conjugates (ADCs) with the potential to not only enhance treatment efficacy but also improve tolerability for patients with B-cell lymphomas. Classic ADCs consist of monoclonal antibodies (mAbs) linked to drugs or toxins. They selectively deliver toxic moieties to tumor cells. As such, they greatly improve the therapeutic index compared to traditional chemotherapeutic agents. However, the therapeutic efficacy and safety of ADCs are dependent on linker stability and payload toxicity. Limited payload number on a single antibody (drug-to-antibody ratio, or DAR) has been driving investigators to use extremely toxic agents; however, even very low off-target binding of these ADCs may kill patients. Herein we report a new design of ADCs that consists of rituximab (RTX) and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–epirubicin conjugates. The latter was selectively attached to RTX via reduced disulfide bonds. Such design allows the introduction of a large payload of drug on the antibody without adding attachment sites and without compromising the antigen-targeting ability. The binding of the new conjugate, namely RTX-P-EPI, to Ramos cells (with high CD20 expression) was confirmed. The cytotoxicity of RTX-P-EPI against Raji and Ramos cells was also determined. Interestingly, two-fold inhibition of cell proliferation was observed when using RTX-P-EPI compared with their equivalent physical mixture of RTX and P-EPI. Treatment of male SCID mice bearing subcutaneous Ramos B-cell lymphoma tumors demonstrated that RTX-P-EPI possessed superior efficacy when compared to combination of RTX with chemotherapy EPI (RTX+EPI) and P-EPI (RTX+P-EPI), whereas single RTX and a non-specific conjugate IgG-P-EPI only showed marginal effect. The conjugate RTX-EPI in which EPI was directly attached to RTX demonstrated much less antitumor activity compared with RTX-P-EPI. The results suggest that this new design possesses synergistic potential of immunotherapy combined with established macromolecular therapy; moreover, a conventional chemo-agent could be utilized to generate highly effective ADCs and to achieve lower risk of off-target toxicity.
Graphical abstract
http://ift.tt/2qjHWq5
Professor Arto Urtti —A northern light from the land of the midnight sun
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
http://ift.tt/2qjFUqe
Six month delivery of GDNF from PLGA/vitamin E biodegradable microspheres after intravitreal injection in rabbits
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Cristina García-Caballero, Esther Prieto-Calvo, Patricia Checa-Casalengua, Elena García-Martín, Vicente Polo-Llorens, Julián García-Feijoo, Irene Teresa Molina-Martínez, Irene Bravo-Osuna, Rocío Herrero-Vanrell
Local long-term delivery of glial cell line derived neurotrophic factor (GDNF) from vitamin E/poly-lactic-co-glycolic acid microspheres (MSs) protects retinal ganglion cells in an animal model of glaucoma for up to 11weeks. However, the pharmacokinetics of GDNF after intravitreal injection of MSs is not known. We evaluated the GDNF levels after a single intravitreal injection of GDNF/VitE MSs. Biodegradable MSs were prepared by the solid-oil-in-water emulsion-solvent evaporation technique and characterized. Rabbits received a single intravitreal injection (50μL) of GDNF/VitE MSs (4%w/v; 24 right eyes; 74.85ng GDNF), blank MSs (4%w/v; 24 left eyes), and balanced salt solution (4 eyes). Two controls eyes received no injections. At 24h, 1, 4, 6, 8, 12, 18, and 24weeks after injection, the eyes were enucleated, and the intravitreal GDNF levels were quantified. Pharmacokinetic data were analysed according to non-compartmental model. Intraocular GDNF levels of 717.1±145.1pg/mL were observed at 24h for GDNF-loaded MSs, followed by a plateau (745.3±25.5pg/mL) until day 28. After that, a second plateau (17.4±3.7pg/mL) occurred from 8 to 24weeks post-injection, significantly higher than the basal levels. Eyes injected with GDNF/vitE and Blank-MSs did not show any abnormalities during the six-months follow up after administration. The single injection of GDNF/VitE MSs provided a sustained controlled release of the neurotrophic factor in a controlled fashion for up to six months.
Graphical abstract
http://ift.tt/2qUR2Xr
Identification of novel MRP3 inhibitors based on computational models and validation using an in vitro membrane vesicle assay
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Izna Ali, Matthew A. Welch, Yang Lu, Peter W. Swaan, Kim L.R. Brouwer
IntroductionMultidrug resistance-associated protein 3 (MRP3), an efflux transporter on the hepatic basolateral membrane, may function as a compensatory mechanism to prevent the accumulation of anionic substrates (e.g., bile acids) in hepatocytes. Inhibition of MRP3 may disrupt bile acid homeostasis and is one hypothesized risk factor for the development of drug-induced liver injury (DILI). Therefore, identifying potential MRP3 inhibitors could help mitigate the occurrence of DILI.MethodsBayesian models were developed using MRP3 transporter inhibition data for 86 structurally diverse drugs. The compounds were split into training and test sets of 57 and 29 compounds, respectively, and six models were generated based on distinct inhibition thresholds and molecular fingerprint methods. The six Bayesian models were validated against the test set and the model with the highest accuracy was utilized for a virtual screen of 1470 FDA-approved drugs from DrugBank. Compounds that were predicted to be inhibitors were selected for in vitro validation. The ability of these compounds to inhibit MRP3 transport at a concentration of 100μM was measured in membrane vesicles derived from stably transfected MRP3-over-expressing HEK-293 cells with [3H]-estradiol-17β-d-glucuronide (E217G; 10μM; 5min uptake) as the probe substrate.ResultsA predictive Bayesian model was developed with a sensitivity of 73% and specificity of 71% against the test set used to evaluate the six models. The area under the Receiver Operating Characteristic (ROC) curve was 0.710 against the test set. The final selected model was based on compounds that inhibited substrate transport by at least 50% compared to the negative control, and functional-class fingerprints (FCFP) with a circular diameter of six atoms, in addition to one-dimensional physicochemical properties. The in vitro screening of predicted inhibitors and non-inhibitors resulted in similar model performance with a sensitivity of 64% and specificity of 70%. The strongest inhibitors of MRP3-mediated E217G transport were fidaxomicin, suramin, and dronedarone. Kinetic assessment revealed that fidaxomicin was the most potent of these inhibitors (IC50=1.83±0.46μM). Suramin and dronedarone exhibited IC50 values of 3.33±0.41 and 47.44±4.41μM, respectively.ConclusionBayesian models are a useful screening approach to identify potential inhibitors of transport proteins. Novel MRP3 inhibitors were identified by virtual screening using the selected Bayesian model, and MRP3 inhibition was confirmed by an in vitro transporter inhibition assay. Information generated using this modeling approach may be valuable in predicting the potential for DILI and/or MRP3-mediated drug-drug interactions.
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Editorial board members
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
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Synthetic nanocarriers for the delivery of polynucleotides to the eye
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Sofia M. Saraiva, Vanessa Castro-López, Covadonga Pañeda, María José Alonso
This review is a comprehensive analysis of the progress made so far on the delivery of polynucleotide-based therapeutics to the eye, using synthetic nanocarriers. Attention has been addressed to the capacity of different nanocarriers for the specific delivery of polynucleotides to both, the anterior and posterior segments of the eye, with emphasis on their ability to (i) improve the transport of polynucleotides across the different eye barriers; (ii) promote their intracellular penetration into the target cells; (iii) protect them against degradation and, (iv) deliver them in a long-term fashion way. Overall, the conclusion is that despite the advantages that nanotechnology may offer to the area of ocular polynucleotide-based therapies (especially AS-ODN and siRNA delivery), the knowledge disclosed so far is still limited. This fact underlines the necessity of more fundamental and product-oriented research for making the way of the said nanotherapies towards clinical translation.
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Effect of hyaluronic acid-binding to lipoplexes on intravitreal drug delivery for retinal gene therapy
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Thomas F Martens, Karen Peynshaert, Thaís Leite Nascimento, Elias Fattal, Marcus Karlstetter, Thomas Langmann, Serge Picaud, Jo Demeester, Stefaan C De Smedt, Katrien Remaut, Kevin Braeckmans
Intravitreal administration of nanomedicines could be valuable for retinal gene therapy, if their mobility in the vitreous and therapeutic efficacy in the target cells can be guaranteed. Hyaluronic acid (HA) as an electrostatic coating of polymeric gene nanomedicines has proven to be beneficial on both accounts. While electrostatic coating provides an easy way of coating cationic nanoparticles, the stability of electrostatic complexes in vivo is uncertain. In this study, therefore, we compare electrostatic with covalent coating of gene nanocarriers with HA for retinal gene therapy via intravitreal administration. Specifically, DOTAP:DOPE/plasmid DNA lipoplexes coated with HA are evaluated in terms of intravitreal mobility using a previously optimized ex vivo model. We find that both electrostatic and covalent HA coating considerably improve the mobility of the lipoplexes in the vitreous humor of excised bovine eyes. In addition we evaluate in vitro uptake and transfection efficiency in ARPE-19 cells. Contrary to PEGylated lipoplexes it is found that HA coated lipoplexes are efficiently internalized into ARPE-19 cells. Covalent HA-coated lipoplexes had an 8-fold increase of transgene expression compared to the uncoated lipoplexes. We conclude that covalent HA-coating of gene nanomedicines is a promising approach for retinal gene therapy by intravitreal administration.
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Expression and splicing of ABC and SLC transporters in the human blood-brain barrier measured with RNAseq
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Adam M. Suhy, Amy Webb, Audrey C. Papp, Ethan G. Geier, Wolfgang Sadee
The blood-brain barrier (BBB) expresses numerous membrane transporters that supply needed nutrients to the central nervous system (CNS), consisting mostly of solute carriers (SLC transporters), or remove unwanted substrates via extrusion pumps through the action of ATP binding cassette (ABC) transporters. Previous work has identified many BBB transporters using hybridization arrays or qRT-PCR, using targeted probes. Here we have performed next-generation sequencing of the transcriptome (RNAseq) extracted from cerebral cortex tissues and brain microvessel endothelial cells (BMEC) obtained from two donors. The same RNA samples had previously been measured for transporter expression using qRT-PCR (Geier et al., 2013), yielding similar expression levels for overlapping mRNAs (R=0.66, p<0.001). RNAseq confirms a number of transporters highly enriched in BMECs (e.g., ABCB1, ABCG2, SLCO2B1, and SLC47A1), but also detects novel BMEC transporters. Multiple splice isoforms detected by RNAseq are either robustly enriched or depleted in BMECs, indicating differential RNA processing in the BBB. The Complete RNAseq data are publically available (GSE94064).
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A structure-activity relationship study of ABCC2 inhibitors
Publication date: 30 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 103
Author(s): Gloria Wissel, Feng Deng, Pavel Kudryavtsev, Leo Ghemtio, Peter Wipf, Henri Xhaard, Heidi Kidron
Multidrug resistance associated protein 2 (MRP2/ABCC2) is a membrane transport protein that can potentially affect the disposition of many substrate drugs and their metabolites. Recently, we studied the interaction of a library of 432 compounds with ABCC2, and the structure-activity relationship (SAR) of a subset of 64 compounds divided into four scaffolds (Wissel, G. et al., 2015. Bioorg Med Chem., 23(13), pp.3513–25). We have now expanded this test set by investigating 114 new compounds, of which 71 are representative of the previous four scaffolds and 43 compounds belong to a new scaffold. Interaction with ABCC2 was assessed by measuring the compounds effect on 5(6)-carboxy-2′,7′-dichlorofluorescein transport in the vesicular transport assay. In line with our previous study, we observed that anionic charge is not essential for inhibition of ABCC2 transport, even though it often increases the inhibitory activity within the analogue series. Additionally, we found that halogen substitutions often increase the inhibitory activity. The results confirm the importance of structural features such as aromaticity and lipophilicity for ABCC2 inhibitory activity.
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Multiple analyses indicate that NR1I3 regulating C6 and TNN may be involved in hip BMD regulation
Source:Journal of Genetics and Genomics
Author(s): Ying-Ying Han, Lan-Juan Zhao, Yong Lin, Hao He, Qing Tian, Wei Zhu, Hui Shen, Xiang-Ding Chen, Hong-Wen Deng
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Attentional blink to alcohol cues in binge drinkers versus non-binge drinkers
Source:Addictive Behaviors, Volume 73
Author(s): Francesco M. DePalma, Natalie Ceballos, Reiko Graham
Previous studies have shown alcohol-related attentional biases in social drinkers; however, the temporal dynamics of these biases are not well understood. The current study examined this issue in 94 participants (27 male) categorized as binge drinkers (BD) or non-binge drinkers (NBD). Two versions of an alcohol-related attentional blink (AB) paradigm were used: one with words and one with images. It was predicted that BDs (versus NBDs) would exhibit reduced AB for alcohol cues, which would be enhanced for the pictorial version of the task (versus words). The relationships between AB and alcohol craving, quantity and frequency of alcohol consumption, symptoms of alcohol use disorder, and family history of alcohol use disorder (AUD) were also examined. While an AB was observed for both alcohol and non-alcohol targets in the NBD group, no AB was found for alcohol targets in the BD group. Furthermore, the magnitude of the AB was related to drinking, such that higher self-reported hazardous drinking was associated with smaller ABs to alcohol-related targets. However, AB was not related to craving or family history of AUD. These results suggest that alcohol-related stimuli are processed more efficiently by BDs, especially those with hazardous alcohol consumption patterns. These results may inform treatment and prevention efforts targeting binge drinkers.
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Associations of blood glucose dynamics with antihyperglycemic treatment and glycemic variability in type 1 and type 2 diabetes
Abstract
Aims
The dynamical structure of glucose fluctuation has largely been disregarded in the contemporary management of diabetes.
Methods
In a retrospective study of patients with diabetes, we evaluated the relationship between glucose dynamics, antihyperglycemic therapy, glucose variability, and glucose exposure, while taking into account potential determinants of the complexity index. We used multiscale entropy (MSE) analysis of continuous glucose monitoring data from 131 subjects with type 1 (n = 18), type 2 diabetes (n = 102), and 11 nondiabetic control subjects. We compared the MSE complexity index derived from the glucose time series among the treatment groups, after adjusting for sex, age, diabetes duration, body mass index, and carbohydrate intake.
Results
In type 2 diabetic patients who were on a diet or insulin regimen with/without oral agents, the MSE index was significantly lower than in nondiabetic subjects but was lowest in the type 1 diabetes group (p < 0.001). The decline in the MSE complexity across the treatment groups correlated with increasing glucose variability and glucose exposure. Statistically, significant correlations existed between higher MSE complexity indices and better glycemic control. In multivariate regression analysis, the antidiabetic therapy was the most powerful predictor of the MSE (β = −0.940 ± 0.242, R 2 = 0.306, p < 0.001), whereas the potential confounders failed to contribute.
Conclusions
The loss of dynamical complexity in glucose homeostasis correlates more closely with therapy modalities and glucose variability than with clinical measures of glycemia. Thus, targeting the glucoregulatory system by adequate therapeutic interventions may protect against progressive worsening of diabetes control.
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Patient-reported outcome measures and patient-reported experience measures
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Antibiotic stewardship in critical care
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Management of acute upper GI bleeding
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Perioperative management of the patient with diabetes requiring emergency surgery
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Perioperative management of opioid-tolerant patients
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IL-33 protects murine viral fulminant hepatitis by targeting coagulation hallmark protein FGL2/fibroleukin expression
Source:Molecular Immunology, Volume 87
Author(s): Haijing Yu, Yang Liu, Jiaquan Huang, Hongwu Wang, Weiming Yan, Dong Xi, Guanxin Shen, Xiaoping Luo, Qin Ning
Fulminant hepatitis (FH) is characterized by rapid liver failure and high mortality. The pathogenesis of viral FH includes virus-induced immune activation, inflammation, and subsequent hepatic apoptosis and necrosis. However, the mechanisms that underlie FH progression are unclear. IL-33 is a member of the IL-1-related cytokines, considered to be an "alarmin" that participates in various diseases, but its precise role in the coagulation of FH is not very clear. In our study, we found that IL-33 is significantly elevated in mice infected with murine hepatitis virus strain 3 (MHV-3). This is accompanied by an increase in pro-coagulant fibrinogen-like protein 2 (FGL2) in the liver. Previous studies have suggested that an increase in FGL2 is diagnostic of FH and liver necrosis, and animals with no FGL2 had better survivorship during FH. Our studies showed that IL-33 administration in a MHV-3 infection promoted survival during FH, with a significant reduction in FGL2 expression and liver inflammation. In vitro IL-33 treatment abrogated MHV-3 and IFN-γ induced FGL2 expression in RAW264.7 and THP-1 cells, respectively. In conclusion, our research suggests that IL-33 protects against viral fulminant hepatitis in mice by antagonizing expression of the pro-coagulant protein FGL2.
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Indocyanine Green Fluorescence-Guided Surgery after IV Injection in Metastatic Colorectal Cancer: A Systematic Review
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Gabriel Liberale, Pierre Bourgeois, Denis Larsimont, Michel Moreau, Vincent Donckier, Takeaki Ishizawa
ObjectiveIndocyanine green fluorescence-guided surgery (ICG-FGS) has emerged as a potential new imaging modality for improving the detection of hepatic, lymph node (LN), and peritoneal metastases in colorectal cancer (CRC) patients. The aim of this paper is to review the available literature in the clinical setting of ICG-FGS for tumoral detection in various fields of metastatic colorectal disease.MethodsPubMed and Medline literature databases were searched for original articles on the use of ICG in the setting of clinical studies on colorectal cancer. The search terms used were "near-infrared fluorescence", "intraoperative imaging", "indocyanine green", "human" and "colorectal cancer".ResultsICG fluorescence imaging (ICG-FI) is clearly supported as an intraoperative technique that allows the detection of additional superficial hepatic metastases of CRC. Data on the role of ICG-FI in the intraoperative detection of peritoneal metastases and LN metastases are scarce but encouraging and ICG-FI could potentially improve the staging and treatment of these patients.ConclusionICG-FI is a promising imaging technique in the detection of small infraclinic LN, hepatic, and peritoneal metastatic deposits that may allow better staging and more complete surgical resection with a potential prognostic benefit for patients.
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Unusual cases of necrotizing fasciitis: a clinical experience from Turkey
Abstract
Background
Necrotizing fasciitis is a rare, destructive soft tissue infection which starts on the skin and subcutaneous tissue, and spreads quickly towards the deeper tissues. Its etiology includes trauma, surgical intervention, perineal abscess, soft tissue infection, minor invasive procedures, abrasion, contusion, burn, laceration, bite, and penetrating injuries. The mortality of the disease can increase in the presence of predisposing factors such as diabetes, hypertension, immunodeficiency, self-care insufficiency, alcoholism, and advanced age. The clinical presentation of necrotizing fasciitis may vary. It is often observed in the abdominal region, the lower extremity, the perineal, perianal, scrotal and genital regions.
Methods
Between December 2011 and September 2016, a retrospective study of all patients admitted due to necrotic wounds and/or tissue defects was undertaken. Their clinical records were reviewed with respect to age, sex, associated morbidities, defect localization, treatment, and outcomes.
Results
Thirteen cases were admitted to the emergency department. There were 10 female and 3 male patients. The defects were located in the gluteal (one), trochanteric (one), thoracic (two), upper extremity (three), lower extremity (two) and perineal region (four). Pressure sores, insect bites, trauma, diabetes mellitus and perineal infections were detected in the etiology of the cases. As observed in our study, NF can present with very different etiological, demographical and clinical findings.
Conclusions
The cases presented some rarely observed characteristics in terms of age, sex, etiology, and infection localization. Therefore, it should be kept in mind that necrotizing fasciitis can exhibit extraordinary characteristics causing confusion with other soft tissue infections, and a detailed and meticulous evaluation must be performed for diagnosis.
Level of Evidence: Level IV, therapeutic study.
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Determinants of Sugar-Sweetened Beverage Consumption among Low-Income Children: Are There Differences by Race/Ethnicity, Age, and Sex?
Publication date: Available online 8 May 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Natasha Tasevska, Derek DeLia, Cori Lorts, Michael Yedidia, Punam Ohri-Vachaspati
BackgroundUnderstanding determinants of high consumption of sugar-sweetened beverages (SSBs), a highly prevalent obesogenic behavior, will help build effective customized public health interventions.ObjectiveOur aim was to identify child and parent lifestyle and household demographic factors predictive of high SSB consumption frequency in children from low-income, ethnically diverse communities that may help inform public health interventions.DesignWe used a cross-sectional telephone household survey.Participants/settingParticipants were 717 boys and 686 girls aged 3 to 18 years old from the New Jersey Childhood Obesity Study living in five low-income cities (Camden, New Brunswick, Newark, Trenton, and Vineland). The adult most knowledgeable about household food shopping completed a questionnaire over the telephone inquiring about their and their child's dietary and physical activity habits, and household-, parent-, and child-level demographics.Main outcome measuresChild's SSB consumption frequency was measured.Statistical analysis performedMultivariate ordered logit models were designed to investigate a variety of variables hypothesized to affect the frequency of SSB consumption. Exploratory stratified analyses by race, sex, and age were also conducted.ResultsEight percent of our study participants never consumed SSBs, 45% consumed SSBs at least once per day, and 23% consumed twice or more per day. SSB consumption was higher among children 12 to 18 years vs 3 to 5 years (P<0.0001), of non-Hispanic black vs non-Hispanic white race/ethnicity (P=0.010), who were moderate fast food consumers vs never consumers (P=0.003), and those whose parents were high vs low SSB consumers (P<0.0001). Living in a non–English-speaking household (P=0.030), having a parent with a college or higher education vs less than high school (P=0.003), and having breakfast 6 to 7 days/wk vs never to 2 days/wk or less were associated with lower SSB consumption (P=0.001).ConclusionsWe identified a number of household-, parent-, and child-level predictors of SSB consumption, which varied by race, sex, and age, useful for building customized interventions targeting certain behaviors in ethnically diverse, low-income children.
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Breast implant associated Anaplastic Large Cell Lymphoma in Australia and New Zealand - high surface area textured implants are associated with increased risk.
Background: The association between breast implants and breast implant associated anaplastic large cell lymphoma (BIA-ALCL), has been confirmed. Implant related risk has been difficult to estimate due to incomplete or unknown implant histories and lack of clarity on the number of implants utilized. Methods: All cases in Australia and New Zealand were identified and analyzed. Textured implants reported in this group were subjected to surface area analysis. Sales data from three leading breast implant manufacturers (Mentor/Allergan/Silimed) dating back to 1999 were secured to estimate implant specific risk. Results: 55 cases of BIA-ALCL were diagnosed in Australia and New Zealand between 2007 and 2016. The mean age of patients was 47.1 and the mean time of implant exposure was 7.46 years. There were 4 deaths in the series related to mass and/or metastatic presentation. All patients were exposed to textured implants. Surface area analysis confirmed that higher surface area was associated with 64 of the 75 implants utilized (85.3%). Biocell salt loss textured (Allergan/Inamed/McGhan) accounted for 58.7% of implants utilized in this series. Comparative analysis showed the risk of developing BIA-ALCL was found to be 14.11 times higher with Biocell textured implants and 10.84 higher with polyurethane (Silimed) textured implants as compared with Siltex textured implants. Conclusion: This study has calculated implant specific risk of BIA-ALCL. Higher surface area textured implants have been shown to significantly increase risk of BIA-ALCL in Australia and New Zealand. We present a unifying hypothesis to explain these observations. (C)2017American Society of Plastic Surgeons
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In vitro study on antagonism mechanism of glutathione, sodium selenite and mercuric chloride
Publication date: 15 August 2017
Source:Talanta, Volume 171
Author(s): Yu Qiao, Xi Huang, Beibei Chen, Man He, Bin Hu
It has been broadly recognized that the antagonism between selenium (Se) and mercury (Hg) can reduce the toxicity of mercury in organism. Glutathione (GSH) can participate in the metabolism of Se and Hg in vivo and promote the formation of low-toxic Hg-Se complexes, which is a vital way of detoxification for Hg. In this paper, the reaction mechanism of GSH-Se(IV) binary system, GSH-Hg(II) binary system and GSH-Se(IV)-Hg(II) ternary system were systematically studied from the aspects of stoichiometry, thermodynamics and kinetics, via hyphenated techniques including high performance liquid chromatography (HPLC)-ultraviolet (UV) detection, HPLC-inductively coupled plasma mass spectrometry (ICP-MS) and HPLC-electrospray ionization mass spectrometry (ESI-MS). For GSH-Se(IV) binary system, selenodiglutathione (GSSeSG) was the crucial intermediate; the reaction was exothermic and irreversible at constant pressure; it followed second-order kinetics with a fast kinetics (rate constant (k)=4534.2mol−1Ls−1). For GSH-Se(IV)-Hg(II) ternary system, GSSeSeSG would form by the extremely weak dissociation of two molecules of GSSeSG; Hg(II) would rapidly coordinate with GSSeSeSG to generate (HgxSey)n(GS)m precipitates. The mechanism of GSH-Se(IV)-Hg(II) antagonism system involves two processes, the competitive combination of Hg and Se with GSH and the formation of (HgxSey)n(GS)m complexes.
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Ambulatory Hemodynamic Monitoring Reduces Heart Failure Hospitalizations in "Real-World" Clinical Practice
AbstractBackground
In the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association [NYHA] Functional Class III Heart Failure Patients) trial, heart failure hospitalization (HFH) rates were lower in patients managed with guidance from an implantable pulmonary artery pressure sensor compared with usual care.
ObjectivesThis study examined the effectiveness of ambulatory hemodynamic monitoring in reducing HFH outside of the clinical trial setting.
MethodsWe conducted a retrospective cohort study using U.S. Medicare claims data from patients undergoing pulmonary artery pressure sensor implantation between June 1, 2014, and December 31, 2015. Rates of HFH during pre-defined periods before and after implantation were compared using the Andersen-Gill extension to the Cox proportional hazards model while accounting for the competing risk of death, ventricular assist device implantation, or cardiac transplantation. Comprehensive heart failure (HF)–related costs were compared over the same periods.
ResultsAmong 1,114 patients receiving implants, there were 1,020 HFHs in the 6 months before, compared with 381 HFHs, 139 deaths, and 17 ventricular assist device implantations and/or transplants in the 6 months after implantation (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.49 to 0.61; p < 0.001). This lower rate of HFH was associated with a 6-month comprehensive HF cost reduction of $7,433 per patient (IQR: $7,000 to $7,884), and was robust in analyses restricted to 6-month survivors. Similar reductions in HFH and costs were noted in the subset of 480 patients with complete data available for 12 months before and after implantation (HR: 0.66; 95% CI: 0.57 to 0.76; p < 0.001).
ConclusionsAs in clinical trials, use of ambulatory hemodynamic monitoring in clinical practice is associated with lower HFH and comprehensive HF costs. These benefits are sustained to 1 year and support the "real-world" effectiveness of this approach to HF management.
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Using Predicted Cardiovascular Disease Risk in Conjunction With Blood Pressure to Guide Antihypertensive Medication Treatment
Abstract
Using cardiovascular disease (CVD) risk instead of or in addition to blood pressure (BP) to guide antihypertensive treatment is an active area of research. The purpose of this review is to provide an overview of studies that could inform this treatment paradigm. We review data from randomized trials on relative and absolute CVD risk reduction that can occur when antihypertensive treatment is guided by CVD risk. We also review population-level data on using CVD risk in conjunction with BP to guide antihypertensive treatment, the broad distribution in CVD risk for people with similar BP levels, and the use of CVD risk for guiding antihypertensive treatment among subgroups including older adults, young adults, and those with diabetes mellitus or chronic kidney disease. In addition, we review potential challenges in implementing antihypertensive treatment recommendations that incorporate CVD risk. In closing, we provide recommendations for using CVD risk in combination with BP to guide antihypertensive treatment.
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Multiple Comorbidities and Response to Cardiac Resynchronization Therapy: MADIT-CRT Long-Term Follow-Up
AbstractBackground
Data regarding cardiac resynchronization therapy (CRT) in patients with multiple comorbidities are limited.
ObjectivesThis study evaluated the association of multiple comorbidities with the benefits of CRT over implantable cardioverter-defibrillator (ICD) alone.
MethodsWe examined 1,214 MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) study patients with left bundle branch block (LBBB) and 0, 1, 2, or ≥3 comorbidities, including renal dysfunction, hypertension (HTN), diabetes, coronary artery disease, history of atrial arrhythmias, history of ventricular arrhythmias, current smoking, and cerebrovascular accident. In an adjusted analysis, we analyzed risk of heart failure (HF) events or death by comorbidity group in all patients and in patients with CRT with defibrillator (CRT-D) versus ICD. Then we examined percent change in left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV ejection fraction, left atrial volume, and LV dyssynchrony at 1-year in CRT-D patients by comorbidity group.
ResultsThere was an inverse relationship between comorbidity burden and improvements in LV end-systolic volume, LV end-diastolic volume, left ventricular ejection fraction, left atrial volume, and LV dyssynchrony. In an adjusted model, there was an increasing risk of death or nonfatal HF events with increasing comorbidity burden regardless of treatment group (p < 0.001). During a mean follow-up of 4.65 years, there was no interaction with respect to comorbidity burden and the benefit of CRT-D versus ICD only for death or nonfatal HF events (interaction p = 0.943). In the groups with greatest comorbidity burden (2 and ≥3), the absolute risk reduction associated with CRT-D over ICD alone appeared greater than that seen for groups with less comorbidity burden (0 and 1).
ConclusionsDuring long-term follow-up of MADIT-CRT study patients with LBBB randomized to CRT-D, there were differences in HF or death risk and in the degree of reverse remodeling among comorbidity groups. However, the burden of comorbidity does not appear to compromise the clinical benefits of CRT-D compared with ICD alone.
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Prognostic Implications of Moderate Aortic Stenosis in Patients With Left Ventricular Systolic Dysfunction
AbstractBackground
Left ventricular (LV) systolic dysfunction and moderate aortic stenosis (AS) are more frequent with advancing age and often coexist. Afterload reduction is the mainstay of pharmacological treatment of heart failure (HF). Aortic valve replacement (AVR) is only formally indicated for symptomatic severe AS.
ObjectivesThis study sought to determine the clinical outcome of patients with concomitant moderate AS and LV systolic dysfunction.
MethodsEchocardiographic and clinical data of patients with moderate AS and LV systolic dysfunction between 2010 and 2015 from 4 large academic institutions were retrospectively analyzed. Moderate AS was defined as aortic valve area between 1.0 and 1.5 cm2 and LV systolic dysfunction defined as LV ejection fraction <50%. The primary endpoint was a composite of all-cause death, AVR, and HF hospitalization.
ResultsA total of 305 patients (mean age 73 ± 11 years; 75% male) were included. The majority were symptomatic at the time of index echocardiogram (New York Heart Association [NYHA] functional class II: 42%; NYHA functional class III: 28%; and NYHA functional class IV: 4%). Ischemic heart disease was present in 72% of patients. At 4-year follow-up, the primary composite endpoint occurred in 61%. The main predictors for the primary endpoint were male sex (p = 0.022), NYHA functional class III or IV (p < 0.001), and peak aortic jet velocity (p < 0.001). The rate of the composite of all-cause death or HF hospitalization was 48%, rate of all-cause death was 36%, and rate of HF hospitalization was 27%. AVR occurred in 24% of patients.
ConclusionsPatients with concomitant moderate AS and LV systolic dysfunction are at high risk for clinical events. Further studies are needed to determine if earlier AVR in these patients might improve clinical outcome.
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Relation of Mitral Valve Surgery Volume to Repair Rate, Durability, and Survival
AbstractBackground
Degenerative mitral valve repair rates remain highly variable, despite established benefits of repair over replacement. The contribution of surgeon-specific factors is poorly defined.
ObjectivesThis study evaluated the influence of surgeon case volume on degenerative mitral valve repair rates and outcomes.
MethodsA mandatory New York State database was queried and 5,475 patients were identified with degenerative mitral disease who underwent mitral valve operations between 2002 and 2013. Mitral repair rates, mitral reoperations within 12 months of repair, and survival were analyzed using multivariable Cox modeling and restricted cubic spline function.
ResultsMedian annual surgeon volume of any mitral operations was 10 (range 1 to 230), with a mean repair rate of 55% (n = 20,797 of 38,128). In the subgroup of patients with degenerative disease, the mean repair rate was 67% (n = 3,660 of 5,475), with a range of 0% to 100%. Mean repair rates ranged from 48% (n = 179 of 370) for surgeons with total annual volumes of ≤10 mitral operations to 77% (n = 1,710 of 2,216) for surgeons with total annual volumes of >50 mitral operations (p < 0.001). Higher total annual surgeon volume was associated with increased repair rates of degenerative mitral valve disease (adjusted odds ratio [OR]: 1.13 for every additional 10 mitral operations; 95% confidence interval [CI]: 1.10 to 1.17; p < 0.001); a steady decrease in reoperation risk until 25 total mitral operations annually; and improved 1-year survival (adjusted hazard ratio: 0.95 for every additional 10 operations; 95% CI: 0.92 to 0.98; p = 0.001). For surgeons with a total annual volume of ≤25 mitral operations, repair rates were higher (63.8%; n = 180 of 282) if they operated in the same institution as a surgeon with total annual mitral volumes of >50 and degenerative mitral valve repair rates of >70%, compared with surgeons operating in the other institutions (51.3%; n = 580 of 1,130) (adjusted OR: 1.79; 95% CI: 1.24 to 2.60; p < 0.001).
ConclusionsThis study suggests that individual surgeon volume is a determinant of not only mitral repair rates, but also freedom from reoperation, and survival. The data from this study support the guideline's concept of reference referral to experienced mitral surgeons to improve outcomes in patients with degenerative mitral valve disease.
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Post-Operative Chylothorax in Patients With Congenital Heart Disease
AbstractBackground
Post-operative chylothorax in patients with congenital heart disease is a challenging problem with substantial morbidity and mortality. Currently, the etiology of chylothorax is poorly understood and treatment options are limited.
ObjectivesThis study aimed to report lymphatic imaging findings, determine the mechanism of chylothorax after cardiac surgery, and analyze the outcomes of lymphatic embolization.
MethodsWe conducted a retrospective review of 25 patients with congenital heart disease and post-operative chylothorax who presented for lymphatic imaging and intervention between July 2012 and August 2016.
ResultsBased on dynamic contrast-enhanced magnetic resonance lymphangiography and intranodal lymphangiography, we identified 3 distinct etiologies of chylothorax: 2 patients (8%) with traumatic leak from a thoracic duct (TD) branch, 14 patients (56%) with pulmonary lymphatic perfusion syndrome (PLPS), and 9 patients (36%) with central lymphatic flow disorder (CLFD), the latter defined as abnormal central lymphatic flow, effusions in more than 1 compartment, and dermal backflow. Patients with traumatic leak and PLPS were combined into 1 group of 16 patients without CLFD, of whom 14 (88%) had an intact TD. Sixteen patients underwent lymphatic intervention, including complete TD embolization. All 16 patients had resolution of chylothorax, with a median of 7.5 days from intervention to chest tube removal and 15 days from intervention to discharge. The 9 patients with CLFD were considered a separate group, of whom 3 (33%) had an intact TD. Seven patients underwent lymphatic intervention but none survived.
ConclusionsMost patients in this study had nontraumatic chylothorax and dynamic contrast-enhanced magnetic resonance lymphangiography was essential to determine etiology. Lymphatic embolization was successful in patients with traumatic leak and PLPS and, thus, should be considered first-line treatment. Interventions in patients with CLFD were not successful to resolve chylothorax and alternate approaches need to be developed.
http://ift.tt/2ps4SQ6
Utility of intraoral stents in external beam radiotherapy for head and neck cancer
Publication date: July–August 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 4
Author(s): Hiroshi Doi, Masao Tanooka, Toshihisa Ishida, Kuniyasu Moridera, Kenji Ichimiya, Kazuo Tarutani, Kazuhiro Kitajima, Masayuki Fujiwara, Hiromitsu Kishimoto, Norihiko Kamikonya
AimThis study aimed to assess the utility and stability of intraoral stent during intensity-modulated radiation therapy (IMRT).BackgroundThe benefits of intraoral stents in radiotherapy are unclear.Materials and methodsWe analyzed 386 setup errors in 12 patients who received IMRT for head and neck cancers without intraoral stents (intraoral stent [−]) and 183 setup errors in 6 patients who received IMRT with intraoral stents (intraoral stent [+]). All patients were matched according to the immobilization method (masks and boards). Setup errors were measured as the distance from the initial setup based on the marking on the skin and mask to the corrected position based on bone matching on cone beam computed tomography.ResultsThe mean interfractional setup errors in the right–left, craniocaudal, anterior–posterior (AP), and three-dimensional (3D) directions were −0.33, 0.08, −0.25, and 2.75mm in the intraoral stent (−) group and −0.37, 0.24, −0.63, and 2.42mm in the intraoral stent (+) group, respectively (P=0.50, 0.65, 0.01, and 0.02, respectively). The systematic errors for the same directions were 0.89, 1.46, 1.15, and 0.88mm in the intraoral stent (−) group and 0.62, 1.69, 0.68, and 0.56mm in the intraoral stents (+) group, respectively. The random errors were 1.43, 1.43, 1.44, and 1.22mm in the intraoral stent (−) group and 1.06, 1.11, 1.05, and 0.92mm in the intraoral stents (+) group, respectively.ConclusionSetup errors can be significantly reduced in the AP and 3D-directions by using intraoral stents.
http://ift.tt/2psgoef
Using Epigenetic Reprogramming to Treat Pediatric Brain Cancer
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Milan G. Chheda, David H. Gutmann
In this issue of Cancer Cell, Nagaraja et al. dissect the molecular mechanisms underlying therapeutic responses to transcriptional disruptors in the fatal pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). Moreover, they identify super-enhancers mediating these effects, highlighting how normal brain developmental programs can be hijacked in cancer.
Teaser
In this issue of Cancer Cell, Nagaraja et al. dissect the molecular mechanisms underlying therapeutic responses to transcriptional disruptors in the fatal pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). Moreover, they identify super-enhancers mediating these effects, highlighting how normal brain developmental programs can be hijacked in cancer.http://ift.tt/2pX4M60
The Tribble with APL: A New Road to Therapy
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Ruaidhrí Carmody, Karen Keeshan
The t(15;17) translocation generates a PML-RARα fusion protein causative for acute promyelocytic leukemia (APL). Li et al. now identify the pseudokinase stress protein TRIB3 as an important factor in APL disease progression and therapy resistance. Targeting the interaction of TRIB3 and PML-RARα using peptide technology provides a novel therapeutic approach.
Teaser
The t(15;17) translocation generates a PML-RARα fusion protein causative for acute promyelocytic leukemia (APL). Li et al. now identify the pseudokinase stress protein TRIB3 as an important factor in APL disease progression and therapy resistance. Targeting the interaction of TRIB3 and PML-RARα using peptide technology provides a novel therapeutic approach.http://ift.tt/2qKcQYt
Tumor Microenvironment: No Effector T Cells without Dendritic Cells
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Christina Pfirschke, Marie Siwicki, Hsin-Wei Liao, Mikael J. Pittet
Successful antitumor immunity is thought to require T cell entry into tumors, though mechanisms regulating this process remain unclear. In this issue of Cancer Cell, Spranger et al. indicate that chemokines produced by intratumoral Batf3 dendritic cells are critical for effector T cell recruitment. The findings have implications for immunotherapy.
Teaser
Successful antitumor immunity is thought to require T cell entry into tumors, though mechanisms regulating this process remain unclear. In this issue of Cancer Cell, Spranger et al. indicate that chemokines produced by intratumoral Batf3 dendritic cells are critical for effector T cell recruitment. The findings have implications for immunotherapy.http://ift.tt/2pnOGyg
Tackling Resistance to PI3K Inhibition by Targeting the Epigenome
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Shany Koren, Mohamed Bentires-Alj
Phosphoinositide-3-kinase (PI3K) pathway inhibitors have emerged as promising therapeutic agents for estrogen receptor (ERα)-positive breast cancers. However, incipient resistance limits the clinical benefit. Toska and colleagues identified that the epigenetic regulator KMT2D enhances ERα activity in BYL719-treated PIK3CA mutant breast cancer, leading to a rationale for targeting the epigenome and PI3K signaling.
Teaser
Phosphoinositide-3-kinase (PI3K) pathway inhibitors have emerged as promising therapeutic agents for estrogen receptor (ERα)-positive breast cancers. However, incipient resistance limits the clinical benefit. Toska and colleagues identified that the epigenetic regulator KMT2D enhances ERα activity in BYL719-treated PIK3CA mutant breast cancer, leading to a rationale for targeting the epigenome and PI3K signaling.http://ift.tt/2qKzRun
IDH Mutation, Competitive Inhibition of FTO, and RNA Methylation
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Sara M. Elkashef, An-Ping Lin, Jamie Myers, Heinz Sill, Daifeng Jiang, Patricia L.M. Dahia, Ricardo C.T. Aguiar
http://ift.tt/2po78qv
A TIAM Double Hit to Oppose YAP/TAZ
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Luca Azzolin, Stefano Piccolo
In this issue of Cancer Cell, Diamantopoulou et al. uncover dual mechanisms of inhibiting YAP/TAZ by TIAM1 that oppose invasiveness of colorectal cancer cells: TIAM1 interacts with TAZ in the cytoplasm to promote TAZ degradation by the destruction complex, whereas it antagonizes binding of TAZ/YAP to TEAD in the nucleus.
Teaser
In this issue of Cancer Cell, Diamantopoulou et al. uncover dual mechanisms of inhibiting YAP/TAZ by TIAM1 that oppose invasiveness of colorectal cancer cells: TIAM1 interacts with TAZ in the cytoplasm to promote TAZ degradation by the destruction complex, whereas it antagonizes binding of TAZ/YAP to TEAD in the nucleus.http://ift.tt/2qKzQ9N
CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Limin Xia, Wenjie Huang, Marina Bellani, Michael M. Seidman, Kaichun Wu, Daiming Fan, Yongzhan Nie, Yi Cai, Yang W. Zhang, Li-Rong Yu, Huili Li, Cynthia A. Zahnow, Wenbing Xie, Ray-Whay Chiu Yen, Feyruz V. Rassool, Stephen B. Baylin
An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks. CHD4 knockdown activates silenced TSGs, revealing their role for blunting colorectal cancer cell proliferation, invasion, and metastases. High CHD4 and 8-OHdG levels plus low expression of TSGs strongly correlates with early disease recurrence and decreased overall survival.
Graphical abstract
Teaser
Xia et al. show that CHD4 is recruited by OGG1 and ZMYND8, respectively, to interact with oxidative DNA damage sites and double-strand breaks. CHD4 recruits repressive chromatin proteins to these sites and helps maintain DNA hypermethylation-associated transcriptional silencing of tumor suppressor genes.http://ift.tt/2po79e3
Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Shihao Zhang, Qinghua Chen, Qingxu Liu, Yuxi Li, Xiufeng Sun, Lixin Hong, Suyuan Ji, Chengyan Liu, Jing Geng, Weiji Zhang, Zhonglei Lu, Zhen-Yu Yin, Yuanyuan Zeng, Kwang-Huei Lin, Qiao Wu, Qiyuan Li, Keiko Nakayama, Keiich I. Nakayama, Xianming Deng, Randy L. Johnson, Liang Zhu, Daming Gao, Lanfen Chen, Dawang Zhou
Polyploidy can lead to aneuploidy and tumorigenesis. Here, we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis. Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling. Acetylated Skp2 is exclusively localized to the cytosol, which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27, leading to mitotic arrest and subsequently cell polyploidy. In addition, the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2, resulting in polyploid cell division, genomic instability, and oncogenesis. Importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.
Graphical abstract
Teaser
Zhang et al. show that Yap promotes polyploidy and polyploid cell growth via Akt signaling and p300-mediated acetylation of Skp2, which causes Skp2 cytosolic retention and differential regulation of p27 and FoxO1/3 stabilities. Dysregulated Hippo-Yap-Skp2 axis is associated with human hepatocellular carcinomas.http://ift.tt/2pnOE9C
RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Xu Chen, Qiuxia Wu, Philippe Depeille, Peirong Chen, Sophie Thornton, Helen Kalirai, Sarah E. Coupland, Jeroen P. Roose, Boris C. Bastian
Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11.
Graphical abstract
Teaser
Chen et al. find that Ras is required for GNAQ-mediated MAPK activation and identify PKC δ,ɛ and RasGRP3 as components of a signaling module necessary and sufficient to activate the Ras/MAPK pathway in GNAQ mutant uveal melanoma (UM). RasGRP3 is selectively overexpressed in response to GNAQ/11 mutations in UM.http://ift.tt/2psi9rG
TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Ke Li, Feng Wang, Wen-Bin Cao, Xiao-Xi Lv, Fang Hua, Bing Cui, Jiao-Jiao Yu, Xiao-Wei Zhang, Shuang Shang, Shan-Shan Liu, Jin-Mei Yu, Ming-Zhe Han, Bo Huang, Ting-Ting Zhang, Xia Li, Jian-Dong Jiang, Zhuo-Wei Hu
Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which antagonizes myeloid differentiation and promotes APL-initiating cell self-renewal. Combined all-trans retinoic acid (ATRA) with arsenic trioxide (As2O3) or chemotherapy dramatically improves the prognosis of APL patients. Here we report that expression of pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARα and suppressing its sumoylation, ubiquitylation, and degradation. This represses PML nuclear body assembly, p53-mediated senescence, and cell differentiation, and supports cellular self-renewal. Genetically inhibiting TRIB3 expression or combination of a peptide disturbing TRIB3/PML-RARα interaction with ATRA/As2O3 eradicates APL by accelerating PML-RARα degradation. Our study provides insight into APL pathogenesis and a potential therapeutic option against APL.
Graphical abstract
Teaser
Li et al. find that TRIB3 promotes acute promyelocytic leukemia (APL) by suppressing PML-RARα degradation and that the TRIB3 level correlates with APL progression and therapeutic resistance. Disrupting the TRIB3/PML-RARα interaction with a peptide in combination with ATRA or As2O3 suppresses APL in vivo.http://ift.tt/2qKqxXL
Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Stefani Spranger, Daisy Dai, Brendan Horton, Thomas F. Gajewski
Effector T cells have the capability of recognizing and killing cancer cells. However, whether tumors can become immune resistant through exclusion of effector T cells from the tumor microenvironment is not known. By using a tumor model resembling non-T cell-inflamed human tumors, we assessed whether adoptive T cell transfer might overcome failed spontaneous priming. Flow cytometric assays combined with intra-vital imaging indicated failed trafficking of effector T cells into tumors. Mechanistically, this was due to the absence of CXCL9/10, which we found to be produced by CD103+ dendritic cells (DCs) in T cell-inflamed tumors. Our data indicate that lack of CD103+ DCs within the tumor microenvironment dominantly resists the effector phase of an anti-tumor T cell response, contributing to immune escape.
Graphical abstract
Teaser
Spranger et al. show that effector T cells from adoptive T cell transfer fail to traffic to a non-T cell-inflamed melanoma model due to lack of CXCL9/10 produced by Batf3-driven dendritic cells that are present in inflamed tumors but absent in non-inflamed tumors. Human melanomas appear to have similar regulation.http://ift.tt/2qKp9nV
Ablation of Key Oncogenic Pathways by RITA-Reactivated p53 Is Required for Efficient Apoptosis
Publication date: 8 May 2017
Source:Cancer Cell, Volume 31, Issue 5
Author(s): Vera V. Grinkevich, Fedor Nikulenkov, Yao Shi, Martin Enge, Wenjie Bao, Alena Maljukova, Angela Gluch, Alexander Kel, Olle Sangfelt, Galina Selivanova
http://ift.tt/2qKmbzC
In Response to “Hypothermia for Neuroprotection in Convulsive Status Epilepticus”
Source:The Journal of Emergency Medicine
Author(s): Stephane Legriel, Matthieu Resche-Rigon, Alain Cariou
http://ift.tt/2ps2OYf
Graphene for the development of the next-generation of biocomposites for dental and medical applications
Source:Dental Materials
Author(s): Han Xie, Tong Cao, Francisco Javier Rodríguez-Lozano, Emma Kim Luong-Van, Vinicius Rosa
ObjectiveGraphene and its derivatives, graphene oxide (GO) and reduced graphene oxide (rGO), are 2D carbon-based materials with remarkable physical, chemical and biological properties. Graphene sheets have high specific surface area and mechanical strength. Moreover, they have been shown to influence the differentiation of stem cells and to improve properties of biomaterials.MethodsHere, we present the recent achievements on the use of graphene and its derivatives to improve properties and enhance bioactivity of biomaterials. We also discuss the biosafety constraints to be solved to translate these carbonaceous materials to the clinic.ResultsGraphene and its derivatives can be functionalized and further modified with several bioactive molecules. They can be combined with several biomaterials used in regenerative and reconstructive dentistry and medicine. The resultant graphene-modified composites often present improved physico-mechanical properties and enhanced bioactivity. Moreover, graphene-modified composites are promising candidates to deliver growth factors, drugs and others bioactive compounds.SignificanceGraphene can improve the physical, chemical and mechanical properties of biomaterials. As it can be functionalized and combined with several biomolecules, graphene holds enormous potential to be used as drug carriers or substrates and scaffolds for cell-based tissue engineering strategies.
http://ift.tt/2qKnBdu
Ventriculo-caval Shunt Migration
Publication date: Available online 8 May 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): M. Elens, P. Astarci
http://ift.tt/2pX1j7y
Seasonal and interannual variations in whole-ecosystem BVOC emissions from a subtropical plantation in China
Source:Atmospheric Environment, Volume 161
Author(s): Jianhui Bai, Alex Guenther, Andrew Turnipseed, Tiffany Duhl, James Greenberg
Measurements of BVOC emissions, ozone concentration and environmental parameters were carried out from May 2013 to January 2016 in a subtropical Pinus plantation in China. Isoprene and monoterpene emissions were measured using a relaxed eddy accumulation (REA) system and a gradient technique on an above-canopy tower. In 2013, isoprene comprised 21.2% of total terpenoid emissions, while α-pinene, camphene, β-pinene and limonene constituting 51.5%, 2.4%, 9.1%, and 13.0% of total emissions, respectively. Monoterpenes together were the dominant VOCs measured contributing 71.6%. α-pinene, camphene, β-pinene and limonene constituted 67.7%, 3.2%, 11.9%, 17.2% of total monoterpene emissions. Isoprene and monoterpene emissions displayed strong diurnal variations, with lower emissions in the morning and late evening, and the highest emissions around noon. BVOC peak emissions typically occurred a few hours after the noon PAR peak. Isoprene and monoterpene emissions varied with season and were the highest in summer, contributing more than half of the total annual emission, and the lowest emissions were in winter. Evident interannual variations of isoprene, monoterpenes and total BVOCs were observed. Compared to 2013, annual BVOC emissions decreased in 2015, associated with decreases of PAR, Temperature, water vapor, and an increase of all substances in gas, liquid and solid phases in the atmospheric column (e.g., S/Q, the ratio of solar scattered radiation to global radiation). Ozone concentration showed clear diurnal variation with PAR, higher around noon and lower in the early morning and late evening. Generally, there were no evident correlations between ozone concentrations and BVOC emissions, or the vertical gradients of ozone concentrations and BVOC concentrations. Under all sky conditions (including cloudy skies), no strong correlations at a high confidence level or very similar variation patterns were observed between any two following parameters, BVOC emissions, PAR, temperature, water vapor, and S/Q. The major factors controlling BVOC emissions were PAR and temperature but biomass burning smoke and phenology (pine florescence) may also play a role. The mean emission factors at standard conditions determined using the MEGAN model emission algorithms and empirical model of BVOC emissions were 0.71 and 1.19 mg m−2 h−1 for isoprene and 1.39 and 1.65 mg m−2 h−1 for total monoterpenes, respectively.
http://ift.tt/2pnW7We
Endovascular stroke treatment: Is it “everybody's cup of tea?”
Kamble Rajeev, Moudgil Sandeep, Gupta Vivek
Annals of Indian Academy of Neurology 2017 20(2):157-158
http://ift.tt/2pWYuDD
Annals of Indian Academy of Neurology 2017 20(2):157-158
http://ift.tt/2pWYuDD
Bupropion and iron for restless leg syndrome: Do they have efficacy similar to ropinirole?
Samir Kumar Praharaj
Annals of Indian Academy of Neurology 2017 20(2):166-167
http://ift.tt/2pYV8Oi
Annals of Indian Academy of Neurology 2017 20(2):166-167
http://ift.tt/2pYV8Oi
Molecular genetics of epilepsy: A clinician's perspective
Vikas Dhiman
Annals of Indian Academy of Neurology 2017 20(2):96-102
Epilepsy is a common neurological problem, and there is a genetic basis in almost 50% of people with epilepsy. The diagnosis of genetic epilepsies makes the patient assured of the reasons of his/her seizures and avoids unnecessary, expensive, and invasive investigations. Last decade has shown tremendous growth in gene sequencing technologies, which have made genetic tests available at the bedside. Whole exome sequencing is now being routinely used in the clinical setting for making a genetic diagnosis. Genetic testing not only makes the diagnosis but also has an effect on the management of the patients, for example, the role of sodium channels blockers in SCN1A+ Dravet syndrome patients and usefulness of ketogenic diet therapy in SLC2A1+ generalized epilepsy patients. Many clinicians in our country have no or limited knowledge about the molecular genetics of epilepsies, types of genetic tests available, how to access them and how to interpret the results. The purpose of this review is to give an overview in this direction and encourage the clinicians to start considering genetic testing as an important investigation along with electroencephalogram and magnetic resonance imaging for better understanding and management of epilepsy in their patients.
http://ift.tt/2pX84X4
Annals of Indian Academy of Neurology 2017 20(2):96-102
Epilepsy is a common neurological problem, and there is a genetic basis in almost 50% of people with epilepsy. The diagnosis of genetic epilepsies makes the patient assured of the reasons of his/her seizures and avoids unnecessary, expensive, and invasive investigations. Last decade has shown tremendous growth in gene sequencing technologies, which have made genetic tests available at the bedside. Whole exome sequencing is now being routinely used in the clinical setting for making a genetic diagnosis. Genetic testing not only makes the diagnosis but also has an effect on the management of the patients, for example, the role of sodium channels blockers in SCN1A+ Dravet syndrome patients and usefulness of ketogenic diet therapy in SLC2A1+ generalized epilepsy patients. Many clinicians in our country have no or limited knowledge about the molecular genetics of epilepsies, types of genetic tests available, how to access them and how to interpret the results. The purpose of this review is to give an overview in this direction and encourage the clinicians to start considering genetic testing as an important investigation along with electroencephalogram and magnetic resonance imaging for better understanding and management of epilepsy in their patients.
http://ift.tt/2pX84X4
Right- versus left-onset Parkinson's disease: Other psychometric parameters
Yassar Abdullah S Alamri
Annals of Indian Academy of Neurology 2017 20(2):162-163
http://ift.tt/2pZ4oSJ
Annals of Indian Academy of Neurology 2017 20(2):162-163
http://ift.tt/2pZ4oSJ
Frederic Andrews Gibbs and the assassination of John Fitzgerald Kennedy
Kalyan B Bhattacharyya
Annals of Indian Academy of Neurology 2017 20(2):103-105
Frederic Gibbs, the peerless expert on electroencephalogrphy was summoned to provide opinion on the EEG tracing of Jack Ruby, who murdered Lee Harvey Oswald, the assassin of John Fitzgerald Kennedy, the American President, in 1963. Gibbs pleaded that the tracing suggested features indicative of psychomotor epilepsy and Ruby killed Oswald in a state of fugue. His view was not agreed upon but Gibbs stood his ground unflinchingly. Subsequent appeals to the higher court spared Ruby from imminent execution and finally he died a natural death from metastatic complications of carcinoma of the lung in 1967.
http://ift.tt/2pWKDgo
Annals of Indian Academy of Neurology 2017 20(2):103-105
Frederic Gibbs, the peerless expert on electroencephalogrphy was summoned to provide opinion on the EEG tracing of Jack Ruby, who murdered Lee Harvey Oswald, the assassin of John Fitzgerald Kennedy, the American President, in 1963. Gibbs pleaded that the tracing suggested features indicative of psychomotor epilepsy and Ruby killed Oswald in a state of fugue. His view was not agreed upon but Gibbs stood his ground unflinchingly. Subsequent appeals to the higher court spared Ruby from imminent execution and finally he died a natural death from metastatic complications of carcinoma of the lung in 1967.
http://ift.tt/2pWKDgo
Limb-girdle muscular dystrophies in India: A review
Satish V Khadilkar, Hinaben Dayalal Faldu, Sarika Bapuso Patil, Rakesh Singh
Annals of Indian Academy of Neurology 2017 20(2):87-95
Limb-girdle muscular dystrophies (LGMDs) are common in India. Information on LGMDs has been gradually evolving in the recent years. This information is scattered in case series and case studies. The aim of this study is to collate available Indian information on LGMDs and put it in perspective. PubMed search using keywords such as limb-girdle muscular dystrophies in India, sarcoglycanopathies, dysferlinopathy, calpainopathy, and GNE myopathy was carried out. The published information on LGMDs in Indian context suggests that dysferlinopathy, calpainopathy, sarcoglycanopathies, and other myopathies such as GNE myopathy are frequently seen in India. Besides these, anecdotal reports of many other forms are available, some with genetic support and others showing immunocytochemical defects. The genotypic information on LGMDs is gradually evolving and founder mutations have been detected in selected populations. Further multicenter studies are necessary to document the incidence and prevalence of these common conditions in India.
http://ift.tt/2pYW1WW
Annals of Indian Academy of Neurology 2017 20(2):87-95
Limb-girdle muscular dystrophies (LGMDs) are common in India. Information on LGMDs has been gradually evolving in the recent years. This information is scattered in case series and case studies. The aim of this study is to collate available Indian information on LGMDs and put it in perspective. PubMed search using keywords such as limb-girdle muscular dystrophies in India, sarcoglycanopathies, dysferlinopathy, calpainopathy, and GNE myopathy was carried out. The published information on LGMDs in Indian context suggests that dysferlinopathy, calpainopathy, sarcoglycanopathies, and other myopathies such as GNE myopathy are frequently seen in India. Besides these, anecdotal reports of many other forms are available, some with genetic support and others showing immunocytochemical defects. The genotypic information on LGMDs is gradually evolving and founder mutations have been detected in selected populations. Further multicenter studies are necessary to document the incidence and prevalence of these common conditions in India.
http://ift.tt/2pYW1WW
Neurological outcomes following suicidal hanging: A prospective study of 101 patients
Mohammed Turab Jawaid, S Deepak Amalnath, D. K. S. Subrahmanyam
Annals of Indian Academy of Neurology 2017 20(2):106-108
Context: Survivors of suicidal hanging can have variable neurological outcomes – from complete recovery to irreversible brain damage. Literature on the neurological outcomes in these patients is confined to retrospective studies and case series. Hence, this prospective study was carried out. Aims: The aim is to study the neurological outcomes in suicidal hanging. Settings and Design: This was a prospective observational study carried out from July 2014 to July 2016. Subjects and Methods: Consecutive patients admitted to the emergency and medicine wards were included in the study. Details of the clinical and radiological findings, course in hospital and at 1 month postdischarge were analyzed. Statistical Analysis Used: Statistical analysis was performed using IBM SPSS advanced statistics 20.0 (SPSS Inc., Chicago, USA). Univariate analysis was performed using Chi-square test for significance and Odd's ratio was calculated. Results: Of the 101 patients, 6 died and 4 had residual neuro deficits. Cervical spine injury was seen in 3 patients. Interestingly, 39 patients could not remember the act of hanging (retrograde amnesia). Hypotension, pulmonary edema, Glasgow coma scale (GCS) score <8 at admission, need for mechanical ventilation, and cerebral edema on plain computed tomography were more in those with amnesia as compared to those with normal memory and these findings were statistically significant. Conclusions: Majority of patients recovered without any sequelae. Routine imaging of cervical spine may not be warranted in all patients, even in those with poor GCS. Retrograde amnesia might be more common than previously believed and further studies are needed to analyze this peculiar feature.
http://ift.tt/2pWUTW0
Annals of Indian Academy of Neurology 2017 20(2):106-108
Context: Survivors of suicidal hanging can have variable neurological outcomes – from complete recovery to irreversible brain damage. Literature on the neurological outcomes in these patients is confined to retrospective studies and case series. Hence, this prospective study was carried out. Aims: The aim is to study the neurological outcomes in suicidal hanging. Settings and Design: This was a prospective observational study carried out from July 2014 to July 2016. Subjects and Methods: Consecutive patients admitted to the emergency and medicine wards were included in the study. Details of the clinical and radiological findings, course in hospital and at 1 month postdischarge were analyzed. Statistical Analysis Used: Statistical analysis was performed using IBM SPSS advanced statistics 20.0 (SPSS Inc., Chicago, USA). Univariate analysis was performed using Chi-square test for significance and Odd's ratio was calculated. Results: Of the 101 patients, 6 died and 4 had residual neuro deficits. Cervical spine injury was seen in 3 patients. Interestingly, 39 patients could not remember the act of hanging (retrograde amnesia). Hypotension, pulmonary edema, Glasgow coma scale (GCS) score <8 at admission, need for mechanical ventilation, and cerebral edema on plain computed tomography were more in those with amnesia as compared to those with normal memory and these findings were statistically significant. Conclusions: Majority of patients recovered without any sequelae. Routine imaging of cervical spine may not be warranted in all patients, even in those with poor GCS. Retrograde amnesia might be more common than previously believed and further studies are needed to analyze this peculiar feature.
http://ift.tt/2pWUTW0
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Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
