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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/28202493/a-klebsiella-pneumoniae-antibiotic-resistance-mechanism-that-subdues-host-defences-and-promotes-virulence
#1
Timothy J Kidd, Grant Mills, Joana Sá-Pessoa, Amy Dumigan, Christian G Frank, José L Insua, Rebecca Ingram, Laura Hobley, José A Bengoechea
Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Recent studies highlight the emergence of multidrug-resistant K. pneumoniae strains which show resistance to colistin, a last-line antibiotic, arising from mutational inactivation of the mgrB regulatory gene. However, the precise molecular resistance mechanisms of mgrB-associated colistin resistance and its impact on virulence remain unclear. Here, we constructed an mgrB gene K. pneumoniae mutant and performed characterisation of its lipid A structure, polymyxin and antimicrobial peptide resistance, virulence and inflammatory responses upon infection...
February 15, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28179359/vegfa-activates-an-epigenetic-pathway-upregulating-ovarian-cancer-initiating-cells
#2
Kibeom Jang, Minsoon Kim, Candace A Gilbert, Fiona Simpkins, Tan A Ince, Joyce M Slingerland
The angiogenic factor, VEGFA, is a therapeutic target in ovarian cancer (OVCA). VEGFA can also stimulate stem-like cells in certain cancers, but mechanisms thereof are poorly understood. Here, we show that VEGFA mediates stem cell actions in primary human OVCA culture and OVCA lines via VEGFR2-dependent Src activation to upregulate Bmi1, tumor spheres, and ALDH1 activity. The VEGFA-mediated increase in spheres was abrogated by Src inhibition or SRC knockdown. VEGFA stimulated sphere formation only in the ALDH1(+) subpopulation and increased OVCA-initiating cells and tumor formation in vivo through Bmi1...
February 8, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28167565/y-rna-fragment-in-extracellular-vesicles-confers-cardioprotection-via-modulation-of-il-10-expression-and-secretion
#3
Linda Cambier, Geoffrey de Couto, Ahmed Ibrahim, Antonio K Echavez, Jackelyn Valle, Weixin Liu, Michelle Kreke, Rachel R Smith, Linda Marbán, Eduardo Marbán
Cardiosphere-derived cells (CDCs) reduce myocardial infarct size via secreted extracellular vesicles (CDC-EVs), including exosomes, which alter macrophage polarization. We questioned whether short non-coding RNA species of unknown function within CDC-EVs contribute to cardioprotection. The most abundant RNA species in CDC-EVs is a Y RNA fragment (EV-YF1); its relative abundance in CDC-EVs correlates with CDC potency in vivo Fluorescently labeled EV-YF1 is actively transferred from CDCs to target macrophages via CDC-EVs...
February 6, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28148555/targeting-toxoplasma-gondii-cpsf3-as-a-new-approach-to-control-toxoplasmosis
#4
Andrés Palencia, Alexandre Bougdour, Marie-Pierre Brenier-Pinchart, Bastien Touquet, Rose-Laurence Bertini, Cristina Sensi, Gabrielle Gay, Julien Vollaire, Véronique Josserand, Eric Easom, Yvonne R Freund, Hervé Pelloux, Philip J Rosenthal, Stephen Cusack, Mohamed-Ali Hakimi
Toxoplasma gondii is an important food and waterborne pathogen causing toxoplasmosis, a potentially severe disease in immunocompromised or congenitally infected humans. Available therapeutic agents are limited by suboptimal efficacy and frequent side effects that can lead to treatment discontinuation. Here we report that the benzoxaborole AN3661 had potent in vitro activity against T. gondii Parasites selected to be resistant to AN3661 had mutations in TgCPSF3, which encodes a homologue of cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3), an endonuclease involved in mRNA processing in eukaryotes...
February 1, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28148554/patient-driven-search-for-rare-disease-therapies-the-fondazione-telethon-success-story-and-the-strategy-leading-to%C3%A2-strimvelis
#5
Lucia Monaco, Lucia Faccio
No abstract text is available yet for this article.
February 1, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28148553/perk-activation-mitigates-tau-pathology-in%C3%A2-vitro-and-in%C3%A2-vivo
#6
Julius Bruch, Hong Xu, Thomas W Rösler, Anderson De Andrade, Peer-Hendrik Kuhn, Stefan F Lichtenthaler, Thomas Arzberger, Konstanze F Winklhofer, Ulrich Müller, Günter U Höglinger
The RNA-like endoplasmic reticulum kinase (PERK) is genetically associated with the tauopathy progressive supranuclear palsy (PSP). To elucidate the functional mechanisms underlying this association, we explored PERK activity in brains of PSP patients and its function in three tauopathy models (cultured human neurons overexpressing 4-repeat wild-type tau or treated with the environmental neurotoxin annonacin, and P301S tau transgenic mice). In vitro, treatment with a pharmacological PERK activator CCT020312 or PERK overexpression reduced tau phosphorylation, tau conformational change and 4-repeat tau isoforms, and increased cell viability...
February 1, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28130275/modulation-of-mtor-signaling-as-a-strategy-for-the-treatment-of-pompe-disease
#7
Jeong-A Lim, Lishu Li, Orian S Shirihai, Kyle M Trudeau, Rosa Puertollano, Nina Raben
Mechanistic target of rapamycin (mTOR) coordinates biosynthetic and catabolic processes in response to multiple extracellular and intracellular signals including growth factors and nutrients. This serine/threonine kinase has long been known as a critical regulator of muscle mass. The recent finding that the decision regarding its activation/inactivation takes place at the lysosome undeniably brings mTOR into the field of lysosomal storage diseases. In this study, we have examined the involvement of the mTOR pathway in the pathophysiology of a severe muscle wasting condition, Pompe disease, caused by excessive accumulation of lysosomal glycogen...
January 27, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28119320/organization-and-function-of-neuronal-circuits-controlling-movement
#8
Silvia Arber
No abstract text is available yet for this article.
January 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28119319/sensing-infection-and-tissue-damage
#9
Caetano Reis E Sousa
No abstract text is available yet for this article.
January 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28100566/loss-of-axin1-drives-acquired-resistance-to-wnt-pathway-blockade-in-colorectal-cancer-cells-carrying-rspo3-fusions
#10
Gabriele Picco, Consalvo Petti, Alessia Centonze, Erica Torchiaro, Giovanni Crisafulli, Luca Novara, Andrea Acquaviva, Alberto Bardelli, Enzo Medico
In colorectal cancer (CRC), WNT pathway activation by genetic rearrangements of RSPO3 is emerging as a promising target. However, its low prevalence severely limits availability of preclinical models for in-depth characterization. Using a pipeline designed to suppress stroma-derived signal, we find that RSPO3 "outlier" expression in CRC samples highlights translocation and fusion transcript expression. Outlier search in 151 CRC cell lines identified VACO6 and SNU1411 cells as carriers of, respectively, a canonical PTPRK(e1)-RSPO3(e2) fusion and a novel PTPRK(e13)-RSPO3(e2) fusion...
January 18, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28069640/sequence-variation-in-ppp1r13l-results-in-a-novel-form-of-cardio-cutaneous-syndrome
#11
Tzipora C Falik-Zaccai, Yiftah Barsheshet, Hanna Mandel, Meital Segev, Avraham Lorber, Shachaf Gelberg, Limor Kalfon, Shani Ben Haroush, Adel Shalata, Liat Gelernter-Yaniv, Sarah Chaim, Dorith Raviv Shay, Morad Khayat, Michal Werbner, Inbar Levi, Yishay Shoval, Galit Tal, Stavit Shalev, Eli Reuveni, Emily Avitan-Hersh, Eugene Vlodavsky, Liat Appl-Sarid, Dorit Goldsher, Reuven Bergman, Zvi Segal, Ora Bitterman-Deutsch, Orly Avni
Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l-knocked down murine cardiomyocytes and hearts of Ppp1r13l-deficient mice...
January 9, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28053183/the-transcription-factor-gata4-promotes-myocardial-regeneration-in-neonatal-mice
#12
Mona Malek Mohammadi, Badder Kattih, Andrea Grund, Natali Froese, Mortimer Korf-Klingebiel, Anna Gigina, Ulrike Schrameck, Carsten Rudat, Qiangrong Liang, Andreas Kispert, Kai C Wollert, Johann Bauersachs, Joerg Heineke
Heart failure is often the consequence of insufficient cardiac regeneration. Neonatal mice retain a certain capability of myocardial regeneration until postnatal day (P)7, although the underlying transcriptional mechanisms remain largely unknown. We demonstrate here that cardiac abundance of the transcription factor GATA4 was high at P1, but became strongly reduced at P7 in parallel with loss of regenerative capacity. Reconstitution of cardiac GATA4 levels by adenoviral gene transfer markedly improved cardiac regeneration after cryoinjury at P7...
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28031255/rock-signaling-promotes-collagen-remodeling-to-facilitate-invasive-pancreatic-ductal-adenocarcinoma-tumor-cell-growth
#13
Nicola Rath, Jennifer P Morton, Linda Julian, Lena Helbig, Shereen Kadir, Ewan J McGhee, Kurt I Anderson, Gabriela Kalna, Margaret Mullin, Andreia V Pinho, Ilse Rooman, Michael S Samuel, Michael F Olson
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a Kras(G12D)/p53(R172H) mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three-dimensional collagen matrices by increasing matrix remodeling activities...
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28028013/how-to-tackle-antimalarial-resistance
#14
Didier Leroy
No abstract text is available yet for this article.
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28028012/genetically-engineered-mouse-models-in-oncology-research-and-cancer-medicine
#15
REVIEW
Kelly Kersten, Karin E de Visser, Martine H van Miltenburg, Jos Jonkers
Genetically engineered mouse models (GEMMs) have contributed significantly to the field of cancer research. In contrast to cancer cell inoculation models, GEMMs develop de novo tumors in a natural immune-proficient microenvironment. Tumors arising in advanced GEMMs closely mimic the histopathological and molecular features of their human counterparts, display genetic heterogeneity, and are able to spontaneously progress toward metastatic disease. As such, GEMMs are generally superior to cancer cell inoculation models, which show no or limited heterogeneity and are often metastatic from the start...
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28011860/reprogramming-derived-gene-cocktail-increases-cardiomyocyte-proliferation-for-heart-regeneration
#16
Yuan-Yuan Cheng, Yu-Ting Yan, David J Lundy, Annie Ha Lo, Yu-Ping Wang, Shu-Chian Ruan, Po-Ju Lin, Patrick Ch Hsieh
Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regulation of several mitosis-related genes at this stage of reprogramming. Several candidate genes were selected and tested for their ability to induce CM proliferation. Delivering a cocktail of three genes, FoxM1, Id1, and Jnk3-shRNA (FIJs), induced CMs to re-enter the cell cycle and complete mitosis and cytokinesis in vitro More importantly, this gene cocktail increased CM proliferation in vivo and significantly improved cardiac function and reduced fibrosis after myocardial infarction...
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28003336/polysialic-acid-blocks-mononuclear-phagocyte-reactivity-inhibits-complement-activation-and-protects-from-vascular-damage-in-the-retina
#17
Marcus Karlstetter, Jens Kopatz, Alexander Aslanidis, Anahita Shahraz, Albert Caramoy, Bettina Linnartz-Gerlach, Yuchen Lin, Anika Lückoff, Sascha Fauser, Katharina Düker, Janine Claude, Yiner Wang, Johannes Ackermann, Tobias Schmidt, Veit Hornung, Christine Skerka, Thomas Langmann, Harald Neumann
Age-related macular degeneration (AMD) is a major cause of blindness in the elderly population. Its pathophysiology is linked to reactive oxygen species (ROS) and activation of the complement system. Sialic acid polymers prevent ROS production of human mononuclear phagocytes via the inhibitory sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC11) receptor. Here, we show that low-dose intravitreal injection of low molecular weight polysialic acid with average degree of polymerization 20 (polySia avDP20) in humanized transgenic mice expressing SIGLEC11 on mononuclear phagocytes reduced their reactivity and vascular leakage induced by laser coagulation...
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28003335/the-ras-related-gtpase-rhob-confers-resistance-to-egfr-tyrosine-kinase-inhibitors-in-non-small-cell-lung-cancer-via-an-akt-dependent-mechanism
#18
Olivier Calvayrac, Julien Mazières, Sarah Figarol, Claire Marty-Detraves, Isabelle Raymond-Letron, Emilie Bousquet, Magali Farella, Estelle Clermont-Taranchon, Julie Milia, Isabelle Rouquette, Nicolas Guibert, Amélie Lusque, Jacques Cadranel, Nathalie Mathiot, Ariel Savina, Anne Pradines, Gilles Favre
Although lung cancer patients harboring EGFR mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI), most of them rapidly relapse. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR-TKI In a series of samples from EGFR-mutated patients, we found that low RHOB expression correlated with a good response to EGFR-TKI treatment while a poor response correlated with high RHOB expression (15...
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28003334/huwe1-is-a-critical-colonic-tumour-suppressor-gene-that-prevents-myc-signalling-dna-damage-accumulation-and-tumour-initiation
#19
Kevin B Myant, Patrizia Cammareri, Michael C Hodder, Jimi Wills, Alex Von Kriegsheim, Balázs Győrffy, Mamun Rashid, Simona Polo, Elena Maspero, Lynsey Vaughan, Basanta Gurung, Evan Barry, Angeliki Malliri, Fernando Camargo, David J Adams, Antonio Iavarone, Anna Lasorella, Owen J Sansom
Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours...
February 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27974353/vegf-blockade-enhances-the-antitumor-effect-of-brafv600e-inhibition
#20
Valentina Comunanza, Davide Corà, Francesca Orso, Francesca Maria Consonni, Emanuele Middonti, Federica Di Nicolantonio, Anton Buzdin, Antonio Sica, Enzo Medico, Dario Sangiolo, Daniela Taverna, Federico Bussolino
The development of resistance remains a major obstacle to long-term disease control in cancer patients treated with targeted therapies. In BRAF-mutant mouse models, we demonstrate that although targeted inhibition of either BRAF or VEGF initially suppresses the growth of BRAF-mutant tumors, combined inhibition of both pathways results in apoptosis, long-lasting tumor responses, reduction in lung colonization, and delayed onset of acquired resistance to the BRAF inhibitor PLX4720. As well as inducing tumor vascular normalization and ameliorating hypoxia, this approach induces remodeling of the extracellular matrix, infiltration of macrophages with an M1-like phenotype, and reduction in cancer-associated fibroblasts...
February 2017: EMBO Molecular Medicine
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