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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/29907596/inflammation-leads-through-pge-ep-3-signaling-to-hdac5-mef2-dependent-transcription-in-cardiac-myocytes
#1
András D Tóth, Richard Schell, Magdolna Lévay, Christiane Vettel, Philipp Theis, Clemens Haslinger, Felix Alban, Stefanie Werhahn, Lina Frischbier, Jutta Krebs-Haupenthal, Dominique Thomas, Hermann-Josef Gröne, Metin Avkiran, Hugo A Katus, Thomas Wieland, Johannes Backs
The myocyte enhancer factor 2 (MEF2) regulates transcription in cardiac myocytes and adverse remodeling of adult hearts. Activators of G protein-coupled receptors (GPCRs) have been reported to activate MEF2, but a comprehensive analysis of GPCR activators that regulate MEF2 has to our knowledge not been performed. Here, we tested several GPCR agonists regarding their ability to activate a MEF2 reporter in neonatal rat ventricular myocytes. The inflammatory mediator prostaglandin E2 (PGE2 ) strongly activated MEF2...
June 15, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29907597/myeloid-p38%C3%AE-signaling-promotes-intestinal-igf-1-production-and-inflammation-associated-tumorigenesis
#2
Catrin Youssif, Monica Cubillos-Rojas, Mònica Comalada, Elisabeth Llonch, Cristian Perna, Nabil Djouder, Angel R Nebreda
The protein kinase p38α plays a key role in cell homeostasis, and p38α signaling in intestinal epithelial cells protects against colitis-induced tumorigenesis. However, little is known on the contribution of p38α signaling in intestinal stromal cells. Here, we show that myeloid cell-specific downregulation of p38α protects mice against inflammation-associated colon tumorigenesis. The reduced tumorigenesis correlates with impaired detection in the colon of crucial chemokines for immune cell recruitment. We identify insulin-like growth factor-1 (IGF-1) as a novel mediator of the p38α pathway in macrophages...
June 14, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29884617/brain-targeted-stem-cell-gene-therapy-corrects-mucopolysaccharidosis-type-ii-via-multiple-mechanisms
#3
Hélène Fe Gleitz, Ai Yin Liao, James R Cook, Samuel F Rowlston, Gabriella Ma Forte, Zelpha D'Souza, Claire O'Leary, Rebecca J Holley, Brian W Bigger
The pediatric lysosomal storage disorder mucopolysaccharidosis type II is caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood-brain barrier. We tested a brain-targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS...
June 8, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29866761/response-to-growth-hormone-in-patients-with-rnpc3-mutations
#4
LETTER
Gabriel Á Martos-Moreno, Lourdes Travieso-Suárez, Jesús Pozo-Román, María T Muñoz-Calvo, Julie A Chowen, Mikko J Frilander, Luis A Pérez-Jurado, Federico G Hawkins, Jesús Argente
No abstract text is available yet for this article.
June 4, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29848757/dynamics-of-multiple-resistance-mechanisms-in-plasma-dna-during-egfr-targeted-therapies-in-non-small-cell-lung-cancer
#5
Dana Wai Yi Tsui, Muhammed Murtaza, Alvin Seng Cheong Wong, Oscar M Rueda, Christopher G Smith, Dineika Chandrananda, Ross A Soo, Hong Liang Lim, Boon Cher Goh, Carlos Caldas, Tim Forshew, Davina Gale, Wei Liu, James Morris, Francesco Marass, Tim Eisen, Tan Min Chin, Nitzan Rosenfeld
Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR -mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer...
May 30, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29844217/the-ampk-agonist-5-aminoimidazole-4-carboxamide-ribonucleotide-aicar-but-not-metformin-prevents-inflammation-associated-cachectic-muscle-wasting
#6
Derek T Hall, Takla Griss, Jennifer F Ma, Brenda Janice Sanchez, Jason Sadek, Anne Marie K Tremblay, Souad Mubaid, Amr Omer, Rebecca J Ford, Nathalie Bedard, Arnim Pause, Simon S Wing, Sergio Di Marco, Gregory R Steinberg, Russell G Jones, Imed-Eddine Gallouzi
Activation of AMPK has been associated with pro-atrophic signaling in muscle. However, AMPK also has anti-inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory-driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα-induced atrophy, while the mitochondrial inhibitor metformin does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin...
May 29, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29789342/clk2-blockade-modulates-alternative-splicing-compromising-myc-driven-breast-tumors
#7
Fernando Salvador, Roger R Gomis
No abstract text is available yet for this article.
May 22, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29789341/a-novel-chchd10-mutation-implicates-a-mia40-dependent-mitochondrial-import-deficit-in-als
#8
Carina Lehmer, Martin H Schludi, Linnea Ransom, Johanna Greiling, Michaela Junghänel, Nicole Exner, Henrick Riemenschneider, Julie van der Zee, Christine Van Broeckhoven, Patrick Weydt, Michael T Heneka, Dieter Edbauer
CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29-year-old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled-coil-helix-coiled-coil-helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild-type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability...
May 22, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29769258/anti-tumor-efficacy-of-a-novel-clk-inhibitor-via-targeting-rna-splicing-and-myc-dependent-vulnerability
#9
Kenichi Iwai, Masahiro Yaguchi, Kazuho Nishimura, Yukiko Yamamoto, Toshiya Tamura, Daisuke Nakata, Ryo Dairiki, Yoichi Kawakita, Ryo Mizojiri, Yoshiteru Ito, Moriteru Asano, Hironobu Maezaki, Yusuke Nakayama, Misato Kaishima, Kozo Hayashi, Mika Teratani, Shuichi Miyakawa, Misa Iwatani, Maki Miyamoto, Michael G Klein, Wes Lane, Gyorgy Snell, Richard Tjhen, Xingyue He, Sai Pulukuri, Toshiyuki Nomura
The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025...
May 16, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29735722/mtdna-heteroplasmy-level-and-copy-number-indicate-disease-burden-in-m-3243a-g-mitochondrial-disease
#10
John P Grady, Sarah J Pickett, Yi Shiau Ng, Charlotte L Alston, Emma L Blakely, Steven A Hardy, Catherine L Feeney, Alexandra A Bright, Andrew M Schaefer, Gráinne S Gorman, Richard Jq McNally, Robert W Taylor, Doug M Turnbull, Robert McFarland
Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N  = 231, urine N  = 235, skeletal muscle N  = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine ( R 2  = 0...
May 7, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29700043/enhancement-of-red-blood-cell-transfusion-compatibility-using-crispr-mediated-erythroblast-gene-editing
#11
Joseph Hawksworth, Timothy J Satchwell, Marjolein Meinders, Deborah E Daniels, Fiona Regan, Nicole M Thornton, Marieangela C Wilson, Johannes Gg Dobbe, Geert J Streekstra, Kongtana Trakarnsanga, Kate J Heesom, David J Anstee, Jan Frayne, Ashley M Toye
Regular blood transfusion is the cornerstone of care for patients with red blood cell (RBC) disorders such as thalassaemia or sickle-cell disease. With repeated transfusion, alloimmunisation often occurs due to incompatibility at the level of minor blood group antigens. We use CRISPR-mediated genome editing of an immortalised human erythroblast cell line (BEL-A) to generate multiple enucleation competent cell lines deficient in individual blood groups. Edits are combined to generate a single cell line deficient in multiple antigens responsible for the most common transfusion incompatibilities: ABO (Bombay phenotype), Rh (Rhnull ), Kell ( K 0 ), Duffy (Duffynull ), GPB (S- s- U- )...
April 26, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29685959/measles-2018-a-tale-of-two-anniversaries
#12
EDITORIAL
Philippe J Sansonetti
No abstract text is available yet for this article.
May 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29674392/cholesterol-metabolism-promotes-b-cell-positioning-during-immune-pathogenesis-of-chronic-obstructive-pulmonary-disease
#13
Jie Jia, Thomas M Conlon, Rim Sj Sarker, Demet Taşdemir, Natalia F Smirnova, Barkha Srivastava, Stijn E Verleden, Gizem Güneş, Xiao Wu, Cornelia Prehn, Jiaqi Gao, Katharina Heinzelmann, Jutta Lintelmann, Martin Irmler, Stefan Pfeiffer, Michael Schloter, Ralf Zimmermann, Martin Hrabé de Angelis, Johannes Beckers, Jerzy Adamski, Hasan Bayram, Oliver Eickelberg, Ali Önder Yildirim
The development of chronic obstructive pulmonary disease (COPD) pathogenesis remains unclear, but emerging evidence supports a crucial role for inducible bronchus-associated lymphoid tissue (iBALT) in disease progression. Mechanisms underlying iBALT generation, particularly during chronic CS exposure, remain to be defined. Oxysterol metabolism of cholesterol is crucial to immune cell localization in secondary lymphoid tissue. Here, we demonstrate that oxysterols also critically regulate iBALT generation and the immune pathogenesis of COPD In both COPD patients and cigarette smoke (CS)-exposed mice, we identified significantly upregulated CH25H and CYP7B1 expression in airway epithelial cells, regulating CS-induced B-cell migration and iBALT formation...
May 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29666146/identification-of-circadian-clock-modulators-from-existing-drugs
#14
T Katherine Tamai, Yusuke Nakane, Wataru Ota, Akane Kobayashi, Masateru Ishiguro, Naoya Kadofusa, Keisuke Ikegami, Kazuhiro Yagita, Yasufumi Shigeyoshi, Masaki Sudo, Taeko Nishiwaki-Ohkawa, Ayato Sato, Takashi Yoshimura
Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet-lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time-consuming. We therefore performed a high-throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period-shortening compound dehydroepiandrosterone (DHEA; also known as prasterone)...
May 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29661911/patl2-is-a-key-actor-of-oocyte-maturation-whose-invalidation-causes-infertility-in-women-and-mice
#15
Marie Christou-Kent, Zine-Eddine Kherraf, Amir Amiri-Yekta, Emilie Le Blévec, Thomas Karaouzène, Béatrice Conne, Jessica Escoffier, Said Assou, Audrey Guttin, Emeline Lambert, Guillaume Martinez, Magalie Boguenet, Selima Fourati Ben Mustapha, Isabelle Cedrin Durnerin, Lazhar Halouani, Ouafi Marrakchi, Mounir Makni, Habib Latrous, Mahmoud Kharouf, Charles Coutton, Nicolas Thierry-Mieg, Serge Nef, Serge P Bottari, Raoudha Zouari, Jean Paul Issartel, Pierre F Ray, Christophe Arnoult
The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2 , a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects, respectively...
May 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29661910/myeloid-cell-deficiency-of-p38%C3%AE-p38%C3%AE-protects-against-candidiasis-and-regulates-antifungal-immunity
#16
Dayanira Alsina-Beauchamp, Alejandra Escós, Pilar Fajardo, Diego González-Romero, Ester Díaz-Mora, Ana Risco, Miguel A Martín-Serrano, Carlos Del Fresno, Jorge Dominguez-Andrés, Noelia Aparicio, Rafal Zur, Natalia Shpiro, Gordon D Brown, Carlos Ardavín, Mihai G Netea, Susana Alemany, Juan J Sanz-Ezquerro, Ana Cuenda
Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans We describe a new TAK1-TPL2-MKK1-ERK1/2 pathway in macrophages, which is activated by Dectin-1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C...
May 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29661909/a-novel-combination-treatment-against-melanoma-with-nras-mutation-and-therapy-resistance
#17
Yanlin Yu
No abstract text is available yet for this article.
May 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29650805/co-targeting-bet-and-mek-as-salvage-therapy-for-mapk-and-checkpoint-inhibitor-resistant-melanoma
#18
Ileabett M Echevarría-Vargas, Patricia I Reyes-Uribe, Adam N Guterres, Xiangfan Yin, Andrew V Kossenkov, Qin Liu, Gao Zhang, Clemens Krepler, Chaoran Cheng, Zhi Wei, Rajasekharan Somasundaram, Giorgos Karakousis, Wei Xu, Jennifer Jd Morrissette, Yiling Lu, Gordon B Mills, Ryan J Sullivan, Miao Benchun, Dennie T Frederick, Genevieve Boland, Keith T Flaherty, Ashani T Weeraratna, Meenhard Herlyn, Ravi Amaravadi, Lynn M Schuchter, Christin E Burd, Andrew E Aplin, Xiaowei Xu, Jessie Villanueva
Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS -mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy...
May 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29626112/amyloid-blood-biomarker-detects-alzheimer-s-disease
#19
Andreas Nabers, Laura Perna, Julia Lange, Ute Mons, Jonas Schartner, Jörn Güldenhaupt, Kai-Uwe Saum, Shorena Janelidze, Bernd Holleczek, Dan Rujescu, Oskar Hansson, Klaus Gerwert, Hermann Brenner
Alzheimer's disease (AD) is currently incurable, but there is general agreement that a minimally invasive blood biomarker for screening in preclinical stages would be crucial for future therapy. Diagnostic tools for detection of AD are either invasive like cerebrospinal fluid (CSF) biomarkers or expensive such as positron emission tomography (PET) scanning. Here, we determine the secondary structure change of amyloid-β (Aβ) in human blood. This change used as blood amyloid biomarker indicates prodromal AD and correlates with CSF AD biomarkers and amyloid PET imaging in the cross-sectional BioFINDER cohort...
May 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29572264/co-targeting-driver-pathways-in-prostate-cancer-two-birds-with-one-stone
#20
Amina Zoubeidi, Martin E Gleave
No abstract text is available yet for this article.
April 2018: EMBO Molecular Medicine
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