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EMBO Molecular Medicine

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https://www.readbyqxmd.com/read/29242210/reversible-immortalisation-enables-genetic-correction-of-human-muscle-progenitors-and-engineering-of-next-generation-human-artificial-chromosomes-for-duchenne-muscular-dystrophy
#1
Sara Benedetti, Narumi Uno, Hidetoshi Hoshiya, Martina Ragazzi, Giulia Ferrari, Yasuhiro Kazuki, Louise Anne Moyle, Rossana Tonlorenzi, Angelo Lombardo, Soraya Chaouch, Vincent Mouly, Marc Moore, Linda Popplewell, Kanako Kazuki, Motonobu Katoh, Luigi Naldini, George Dickson, Graziella Messina, Mitsuo Oshimura, Giulio Cossu, Francesco Saverio Tedesco
Transferring large or multiple genes into primary human stem/progenitor cells is challenged by restrictions in vector capacity, and this hurdle limits the success of gene therapy. A paradigm is Duchenne muscular dystrophy (DMD), an incurable disorder caused by mutations in the largest human gene: dystrophin. The combination of large-capacity vectors, such as human artificial chromosomes (HACs), with stem/progenitor cells may overcome this limitation. We previously reported amelioration of the dystrophic phenotype in mice transplanted with murine muscle progenitors containing a HAC with the entire dystrophin locus (DYS-HAC)...
December 14, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29229785/the-chemokine-receptor-cx3cr1-coordinates-monocyte-recruitment-and-endothelial-regeneration-after-arterial-injury
#2
Tobias Getzin, Kashyap Krishnasamy, Jaba Gamrekelashvili, Tamar Kapanadze, Anne Limbourg, Christine Häger, L Christian Napp, Johann Bauersachs, Hermann Haller, Florian P Limbourg
Regeneration of arterial endothelium after injury is critical for the maintenance of normal blood flow, cell trafficking, and vascular function. Using mouse models of carotid injury, we show that the transition from a static to a dynamic phase of endothelial regeneration is marked by a strong increase in endothelial proliferation, which is accompanied by induction of the chemokine CX3CL1 in endothelial cells near the wound edge, leading to progressive recruitment of Ly6Clo monocytes expressing high levels of the cognate CX3CR1 chemokine receptor...
December 11, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29217661/foxo3-an-important-player-in-fibrogenesis-and-therapeutic-target-for-idiopathic-pulmonary-fibrosis
#3
Hamza M Al-Tamari, Swati Dabral, Anja Schmall, Pouya Sarvari, Clemens Ruppert, Jihye Paik, Ronald A DePinho, Friedrich Grimminger, Oliver Eickelberg, Andreas Guenther, Werner Seeger, Rajkumar Savai, Soni S Pullamsetti
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo-cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro-fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF-β1)...
December 7, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29217660/chimeric-pneumoviridae-fusion-proteins-as-immunogens-to-induce-cross-neutralizing-antibody-responses
#4
Eduardo Olmedillas, Olga Cano, Isidoro Martínez, Daniel Luque, María C Terrón, Jason S McLellan, José A Melero, Vicente Más
Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV), two members of the Pneumoviridae family, account for the majority of severe lower respiratory tract infections worldwide in very young children. They are also a frequent cause of morbidity and mortality in the elderly and immunocompromised adults. High levels of neutralizing antibodies, mostly directed against the viral fusion (F) glycoprotein, correlate with protection against either hRSV or hMPV However, no cross-neutralization is observed in polyclonal antibody responses raised after virus infection or immunization with purified F proteins...
December 7, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29212784/an-oligoclonal-antibody-durably-overcomes-resistance-of-lung-cancer-to-third-generation-egfr-inhibitors
#5
Maicol Mancini, Hilah Gal, Nadège Gaborit, Luigi Mazzeo, Donatella Romaniello, Tomer Meir Salame, Moshit Lindzen, Georg Mahlknecht, Yehoshua Enuka, Dominick Ga Burton, Lee Roth, Ashish Noronha, Ilaria Marrocco, Dan Adreka, Raya Eilam Altstadter, Emilie Bousquet, Julian Downward, Antonio Maraver, Valery Krizhanovsky, Yosef Yarden
Epidermal growth factor receptor (EGFR) mutations identify patients with lung cancer who derive benefit from kinase inhibitors. However, most patients eventually develop resistance, primarily due to the T790M second-site mutation. Irreversible inhibitors (e.g., osimertinib/AZD9291) inhibit T790M-EGFR, but several mechanisms, including a third-site mutation, C797S, confer renewed resistance. We previously reported that a triple mixture of monoclonal antibodies, 3×mAbs, simultaneously targeting EGFR, HER2, and HER3, inhibits T790M-expressing tumors...
December 6, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29208638/the-diphenylpyrazole-compound-anle138b-blocks-a%C3%AE-channels-and-rescues-disease-phenotypes-in-a-mouse-model-for-amyloid-pathology
#6
Ana Martinez Hernandez, Hendrik Urbanke, Alan L Gillman, Joon Lee, Sergey Ryazanov, Hope Y Agbemenyah, Eva Benito, Gaurav Jain, Lalit Kaurani, Gayane Grigorian, Andrei Leonov, Nasrollah Rezaei-Ghaleh, Petra Wilken, Fernando Teran Arce, Jens Wagner, Martin Fuhrman, Mario Caruana, Angelique Camilleri, Neville Vassallo, Markus Zweckstetter, Roland Benz, Armin Giese, Anja Schneider, Martin Korte, Ratnesh Lal, Christian Griesinger, Gregor Eichele, Andre Fischer
Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ-oligomer structure...
December 5, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29208637/could-blocking-the-formation-of-amyloid-channels-rescue-alzheimer-s-phenotype
#7
Francesc X Guix, Carlos G Dotti
No abstract text is available yet for this article.
December 5, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29191947/a-proteomic-network-approach-across-the-als-ftd-disease-spectrum-resolves-clinical-phenotypes-and-genetic-vulnerability-in-human-brain
#8
Mfon E Umoh, Eric B Dammer, Jingting Dai, Duc M Duong, James J Lah, Allan I Levey, Marla Gearing, Jonathan D Glass, Nicholas T Seyfried
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry-based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD Our systems-level analysis of the brain proteome integrated both differential expression and co-expression approaches to assess the relationship of these differences to clinical and pathological phenotypes...
November 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29191946/thrombopoietin-tickling-the-hsc-s-fancy
#9
Ah Ram Kim, Vijay G Sankaran
No abstract text is available yet for this article.
November 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29191945/thrombopoietin-mutation-in-congenital-amegakaryocytic-thrombocytopenia-treatable-with%C3%A2-romiplostim
#10
Alessandro Pecci, Iman Ragab, Valeria Bozzi, Daniela De Rocco, Serena Barozzi, Tania Giangregorio, Heba Ali, Federica Melazzini, Mohamed Sallam, Caterina Alfano, Annalisa Pastore, Carlo L Balduini, Anna Savoia
Congenital amegakaryocytic thrombocytopenia (CAMT) is an inherited disorder characterized at birth by thrombocytopenia with reduced megakaryocytes, which evolves into generalized bone marrow aplasia during childhood. Although CAMT is genetically heterogeneous, mutations of MPL, the gene encoding for the receptor of thrombopoietin (THPO), are the only known disease-causing alterations. We identified a family with three children affected with CAMT caused by a homozygous mutation (p.R119C) of the THPO gene. Functional studies showed that p...
November 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29183916/ceruloplasmin-replacement-therapy-ameliorates-neurological-symptoms-in-a-preclinical-model-of%C3%A2-aceruloplasminemia
#11
Alan Zanardi, Antonio Conti, Marco Cremonesi, Patrizia D'Adamo, Enrica Gilberti, Pietro Apostoli, Carlo Vittorio Cannistraci, Alberto Piperno, Samuel David, Massimo Alessio
Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin-knockout (CpKO) mouse model of aceruloplasminemia...
November 28, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29180355/photoreceptor-glucose-metabolism-determines-normal-retinal-vascular-growth
#12
Zhongjie Fu, Chatarina A Löfqvist, Raffael Liegl, Zhongxiao Wang, Ye Sun, Yan Gong, Chi-Hsiu Liu, Steven S Meng, Samuel B Burnim, Ivana Arellano, My T Chouinard, Rubi Duran, Alexander Poblete, Steve S Cho, James D Akula, Michael Kinter, David Ley, Ingrid Hansen Pupp, Saswata Talukdar, Ann Hellström, Lois Eh Smith
The neural cells and factors determining normal vascular growth are not well defined even though vision-threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation...
November 27, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29180354/patients-with-rare-diseases-from-therapeutic-orphans-to-pioneers-of-personalized-treatments
#13
Christoph Klein, William A Gahl
No abstract text is available yet for this article.
November 27, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29175945/targeting-rna-g-quadruplexes-as-new-treatment-strategy-for-c9orf72-als-ftd
#14
Martin H Schludi, Dieter Edbauer
No abstract text is available yet for this article.
November 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29138229/genomic-structural-variations-lead-to-dysregulation-of-important-coding-and-non-coding-rna-species-in-dilated-cardiomyopathy
#15
Jan Haas, Stefan Mester, Alan Lai, Karen S Frese, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Tobias Rausch, Rouven Nietsch, Jes-Niels Boeckel, Avisha Carstensen, Mirko Völkers, Carsten Dietrich, Dietmar Pils, Ali Amr, Daniel B Holzer, Diana Martins Bordalo, Daniel Oehler, Tanja Weis, Derliz Mereles, Sebastian Buss, Eva Riechert, Emil Wirsz, Maximilian Wuerstle, Jan O Korbel, Andreas Keller, Hugo A Katus, Andreas E Posch, Benjamin Meder
The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non-coding RNAs. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome-wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all classes of gene transcripts (e...
November 14, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29127101/fighting-vessel-dysmorphia-to-improve-glioma-chemotherapy
#16
Marja Lohela, Kari Alitalo
No abstract text is available yet for this article.
November 10, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29113976/co-infection-with-chikungunya-virus-alters-trafficking-of-pathogenic-cd8-t-cells-into-the-brain-and-prevents-plasmodium-induced-neuropathology
#17
Teck-Hui Teo, Shanshan W Howland, Carla Claser, Sin Yee Gun, Chek Meng Poh, Wendy Wl Lee, Fok-Moon Lum, Lisa Fp Ng, Laurent Rénia
Arboviral diseases have risen significantly over the last 40 years, increasing the risk of co-infection with other endemic disease such as malaria. However, nothing is known about the impact arboviruses have on the host response toward heterologous pathogens during co-infection. Here, we investigate the effects of Chikungunya virus (CHIKV) co-infection on the susceptibility and severity of malaria infection. Using the Plasmodium berghei ANKA (PbA) experimental cerebral malaria (ECM) model, we show that concurrent co-infection induced the most prominent changes in ECM manifestation...
November 7, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29113975/g-quadruplex-binding-small-molecules-ameliorate-c9orf72-ftd-als-pathology-in%C3%A2-vitro-and-in%C3%A2-vivo
#18
Roberto Simone, Rubika Balendra, Thomas G Moens, Elisavet Preza, Katherine M Wilson, Amanda Heslegrave, Nathan S Woodling, Teresa Niccoli, Javier Gilbert-Jaramillo, Samir Abdelkarim, Emma L Clayton, Mica Clarke, Marie-Therese Konrad, Andrew J Nicoll, Jamie S Mitchell, Andrea Calvo, Adriano Chio, Henry Houlden, James M Polke, Mohamed A Ismail, Chad E Stephens, Tam Vo, Abdelbasset A Farahat, W David Wilson, David W Boykin, Henrik Zetterberg, Linda Partridge, Selina Wray, Gary Parkinson, Stephen Neidle, Rickie Patani, Pietro Fratta, Adrian M Isaacs
Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA-binding proteins and through toxic dipeptide repeat proteins generated by repeat-associated non-ATG translation. GGGGCC repeat RNA folds into a G-quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy...
November 7, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29109127/a-complex-genomic-locus-drives-mtdna-replicase-polg-expression-to-its-disease-related-nervous-system-regions
#19
Joni Nikkanen, Juan Cruz Landoni, Diego Balboa, Maarja Haugas, Juha Partanen, Anders Paetau, Pirjo Isohanni, Virginia Brilhante, Anu Suomalainen
DNA polymerase gamma (POLG), the mtDNA replicase, is a common cause of mitochondrial neurodegeneration. Why POLG defects especially cause central nervous system (CNS) diseases is unknown. We discovered a complex genomic regulatory locus for POLG, containing three functional CNS-specific enhancers that drive expression specifically in oculomotor complex and sensory interneurons of the spinal cord, completely overlapping with the regions showing neuronal death in POLG patients. The regulatory locus also expresses two functional RNAs, LINC00925-RNA and MIR9-3, which are coexpressed with POLG The MIR9-3 targets include NR2E1, a transcription factor maintaining neural stem cells in undifferentiated state, and MTHFD2, the regulatory enzyme of mitochondrial folate cycle, linking POLG expression to stem cell differentiation and folate metabolism...
November 6, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29084756/akt-inhibition-improves-long-term-tumour-control-following-radiotherapy-by-altering-the-microenvironment
#20
Emma J Searle, Brian A Telfer, Debayan Mukherjee, Duncan M Forster, Barry R Davies, Kaye J Williams, Ian J Stratford, Tim M Illidge
Radiotherapy is an important anti-cancer treatment, but tumour recurrence remains a significant clinical problem. In an effort to improve outcomes further, targeted anti-cancer drugs are being tested in combination with radiotherapy. Here, we have studied the effects of Akt inhibition with AZD5363. AZD5363 administered as an adjuvant after radiotherapy to FaDu and PE/CA PJ34 tumours leads to long-term tumour control, which appears to be secondary to effects on the irradiated tumour microenvironment. AZD5363 reduces the downstream effectors VEGF and HIF-1α, but has no effect on tumour vascularity or oxygenation, or on tumour control, when administered prior to radiotherapy...
October 30, 2017: EMBO Molecular Medicine
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