Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL ‐10 expression and secretion
Abstract
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. Direct transfection of macrophages with EV‐YF1 induced transcription and ...
Source: EMBO Molecular Medicine - January 31, 2017 Category: Molecular Biology Authors: Linda Cambier, Geoffrey Couto, Ahmed Ibrahim, Antonio K Echavez, Jackelyn Valle, Weixin Liu, Michelle Kreke, Rachel R Smith, Linda Marb án, Eduardo Marbán Tags: Research Article Source Type: research
Patient ‐driven search for rare disease therapies: the Fondazione Telethon success story and the strategy leading to Strimvelis
The recent approval of Strimvelis, the first ex vivo gene therapy to gain marketing authorization (Schimmer & Breazzano, ), has drawn attention to Fondazione Telethon, the Italian charity that played a pivotal role in this effort. Although it is not uncommon that advanced therapies, such as Strimvelis, are developed by partnerships between academia and industry, direct involvement of a charity in key steps of this process is still unusual. Illustrating the strategies and operational model adopted by Fondazione Telethon to achieve its mission of supporting excellent research aimed at curing rare genetic diseases may el...
Source: EMBO Molecular Medicine - January 31, 2017 Category: Molecular Biology Authors: Lucia Monaco, Lucia Faccio Tags: Commentary Source Type: research
PERK activation mitigates tau pathology in vitro and in vivo
Abstract
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 isofo...
Source: EMBO Molecular Medicine - January 31, 2017 Category: Molecular Biology Authors: Julius Bruch, Hong Xu, Thomas W R ösler, Anderson De Andrade, Peer‐Hendrik Kuhn, Stefan F Lichtenthaler, Thomas Arzberger, Konstanze F Winklhofer, Ulrich Müller, Günter U Höglinger Tags: Research Article Source Type: research
Organization and function of neuronal circuits controlling movement
The 2017 Louis‐Jeantet Prize for Medicine winner Silvia Arber describes her laboratory's contributions to our understanding of the neuronal circuits underlying the control of movement in mammals. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - January 23, 2017 Category: Molecular Biology Authors: Silvia Arber Tags: Louis ‐Jeantet Prize Winner: Commentary Source Type: research
Modulation of mTOR signaling as a strategy for the treatment of Pompe disease
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. Here, we report the dysregulation of mTOR signaling in the diseased muscle cells, and we focus on potential sites for therapeutic intervention. Reactivation of mTOR in the whole muscle of Pompe mice by TSC knockdown resulted in the reversal of atrophy and a striking removal of autophagic buildup. Of particular interest, we found that the aberrant mTOR signaling can be reversed by arginine. This finding can be translated into t...
Source: EMBO Molecular Medicine - December 31, 2016 Category: Molecular Biology Authors: Jeong ‐A Lim, Lishu Li, Orian S Shirihai, Kyle M Trudeau, Rosa Puertollano, Nina Raben Tags: Research Article Source Type: research
Sensing infection and tissue damage
Innate and adaptive immunity work concertedly in vertebrates to restore homoeostasis following pathogen invasion or other insults. Like all homoeostatic circuits, immunity relies on an integrated system of sensors, transducers and effectors that can be analysed in cellular or molecular terms. At the cellular level, T and B lymphocytes act as an effector arm of immunity that is mobilised in response to signals transduced by innate immune cells that detect a given insult. These innate cells are spread around the body and include dendritic cells (DCs), the chief immune sensors of pathogen invasion and tumour growth. At the mo...
Source: EMBO Molecular Medicine - December 31, 2016 Category: Molecular Biology Authors: Caetano Reis e Sousa Tags: Louis ‐Jeantet Prize Winner: Commentary Source Type: research
Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions
Abstract
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. Both lines displayed ...
Source: EMBO Molecular Medicine - December 31, 2016 Category: Molecular Biology Authors: Gabriele Picco, Consalvo Petti, Alessia Centonze, Erica Torchiaro, Giovanni Crisafulli, Luca Novara, Andrea Acquaviva, Alberto Bardelli, Enzo Medico Tags: Report Source Type: research
The transcription factor GATA4 promotes myocardial regeneration in neonatal mice
Abstract
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. In contrast, the myocardial scar was larger in cardiomyocyte‐specif...
Source: EMBO Molecular Medicine - December 31, 2016 Category: Molecular Biology Authors: 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 Tags: Research Article Source Type: research
How to tackle antimalarial resistance?
In the context of drug resistance, malaria is no exception. Even the latest artemisinins have started to lose their full efficacy in patients. Didier Leroy tells us about the strategies adopted by Medicines for Malaria Venture to reduce this terrible culprit. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - December 26, 2016 Category: Molecular Biology Authors: Didier Leroy Tags: Opinion Source Type: research
PD ‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered a non‐immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD‐L1 expression in a JAK/Stat1‐dependent manner. In vitro, PD‐L1 inhibition did not alter radio‐ and chemosensitivity. In vivo, addition of anti‐PD‐L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensiti...
Source: EMBO Molecular Medicine - December 7, 2016 Category: Molecular Biology Authors: Abul Azad, Su Yin Lim, Zenobia D'Costa, Keaton Jones, Angela Diana, Owen J Sansom, Philipp Kruger, Stanley Liu, W Gillies McKenna, Omer Dushek, Ruth J Muschel, Emmanouil Fokas Tags: Research Article Source Type: research
ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth
Abstract
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 KrasG12D/p53R172H 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. RNA se...
Source: EMBO Molecular Medicine - November 30, 2016 Category: Molecular Biology Authors: 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 Tags: Research Article Source Type: research
Genetically engineered mouse models in oncology research and cancer medicine
Abstract
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. Given that GEMM...
Source: EMBO Molecular Medicine - November 30, 2016 Category: Molecular Biology Authors: Kelly Kersten, Karin E Visser, Martine H Miltenburg, Jos Jonkers Tags: Review Source Type: research
Reprogramming ‐derived gene cocktail increases cardiomyocyte proliferation for heart regeneration
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 reduc...
Source: EMBO Molecular Medicine - November 30, 2016 Category: Molecular Biology Authors: Yuan ‐Yuan Cheng, Yu‐Ting Yan, David J Lundy, Annie HA Lo, Yu‐Ping Wang, Shu‐Chian Ruan, Po‐Ju Lin, Patrick CH Hsieh Tags: Research Article Source Type: research
VEGF blockade enhances the antitumor effect of BRAFV600E inhibition
Abstract
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...
Source: EMBO Molecular Medicine - November 30, 2016 Category: Molecular Biology Authors: Valentina Comunanza, Davide Cor à, Francesca Orso, Francesca Maria Consonni, Emanuele Middonti, Federica Di Nicolantonio, Anton Buzdin, Antonio Sica, Enzo Medico, Dario Sangiolo, Daniela Taverna, Federico Bussolino Tags: Research Article Source Type: research
Immune checkpoint blockade can synergize with radiation therapy, even in tumors resistant to checkpoint monotherapy
Immunotherapy has evolved as a new pillar of cancer treatment during the last decade. The main breakthrough was the development of immune checkpoint blocking (ICB) antibodies, which antagonize inhibitory receptors on T cells and their ligands and thus unleash the cellular immune system against the tumor. ICB showed tremendous effects in several types of cancer. However, only a proportion of the patients suffering from tumors, which are in principle sensitive, benefit from this treatment and other kinds of neoplasia are completely resistant. Great effort is currently being undertaken to distinguish responders from non‐res...
Source: EMBO Molecular Medicine - November 30, 2016 Category: Molecular Biology Authors: Jan D örrie Tags: News & Views Source Type: research
