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EMBO Molecular Medicine

Hanibal Bohnenberger, Lars Kaderali, Philipp Ströbel, Diego Yepes, Uwe Plessmann, Neekesh V Dharia, Sha Yao, Carina Heydt, Sabine Merkelbach-Bruse, Alexander Emmert, Jonatan Hoffmann, Julius Bodemeyer, Kirsten Reuter-Jessen, Anna-Maria Lois, Leif Hendrik Dröge, Philipp Baumeister, Christoph Walz, Lorenz Biggemann, Roland Walter, Björn Häupl, Federico Comoglio, Kuan-Ting Pan, Sebastian Scheich, Christof Lenz, Stefan Küffer, Felix Bremmer, Julia Kitz, Maren Sitte, Tim Beißbarth, Marc Hinterthaner, Martin Sebastian, Joachim Lotz, Hans-Ulrich Schildhaus, Hendrik Wolff, Bernhard C Danner, Christian Brandts, Reinhard Büttner, Martin Canis, Kimberly Stegmaier, Hubert Serve, Henning Urlaub, Thomas Oellerich
Patients with head-and-neck cancer can develop both lung metastasis and primary lung cancer during the course of their disease. Despite the clinical importance of discrimination, reliable diagnostic biomarkers are still lacking. Here, we have characterised a cohort of squamous cell lung (SQCLC) and head-and-neck (HNSCC) carcinomas by quantitative proteomics. In a training cohort, we quantified 4,957 proteins in 44 SQCLC and 30 HNSCC tumours. A total of 518 proteins were found to be differentially expressed between SQCLC and HNSCC, and some of these were identified as genetic dependencies in either of the two tumour types...
August 10, 2018: EMBO Molecular Medicine
Huixin Xu, Molly M Rajsombath, Pia Weikop, Dennis J Selkoe
Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE's anti-inflammatory protection of brain microglia against soluble oligomers of human amyloid β-protein (oAβ). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced β-adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the β-adrenergic agonist isoproterenol experienced similar protection of microglia against oAβ-induced inflammation as did mice in EE Conversely, mice in EE fed the β-adrenergic antagonist propranolol lost microglial protection against oAβ...
August 9, 2018: EMBO Molecular Medicine
John B Appleby, Annelien L Bredenoord
No abstract text is available yet for this article.
August 7, 2018: EMBO Molecular Medicine
Nevenka Dudvarski Stanković, Frank Bicker, Stefanie Keller, David Tw Jones, Patrick N Harter, Arne Kienzle, Clarissa Gillmann, Philipp Arnold, Anna Golebiewska, Olivier Keunen, Alf Giese, Andreas von Deimling, Tobias Bäuerle, Simone P Niclou, Michel Mittelbronn, Weilan Ye, Stefan M Pfister, Mirko Hh Schmidt
Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti-VEGF (vascular endothelial growth factor) blocking antibodies such as bevacizumab. Although its application in human GBM only increased progression-free periods but did not improve overall survival, physicians and researchers still utilize this treatment option due to the lack of adequate alternatives...
July 31, 2018: EMBO Molecular Medicine
Cristina Migliore, Elena Morando, Elena Ghiso, Sergio Anastasi, Vera P Leoni, Maria Apicella, Davide Cora', Anna Sapino, Filippo Pietrantonio, Filippo De Braud, Amedeo Columbano, Oreste Segatto, Silvia Giordano
The onset of secondary resistance represents a major limitation to long-term efficacy of target therapies in cancer patients. Thus, the identification of mechanisms mediating secondary resistance is the key to the rational design of therapeutic strategies for resistant patients. MiRNA profiling combined with RNA-Seq in MET-addicted cancer cell lines led us to identify the miR-205/ERRFI1 (ERBB receptor feedback inhibitor-1) axis as a novel mediator of resistance to MET tyrosine kinase inhibitors (TKIs). In cells resistant to MET-TKIs, epigenetically induced miR-205 expression determined the downregulation of ERRFI1 which, in turn, caused EGFR activation, sustaining resistance to MET-TKIs...
July 18, 2018: EMBO Molecular Medicine
Claudia V Pereira, Sandra R Bacman, Tania Arguello, Ugne Zekonyte, Sion L Williams, David R Edgell, Carlos T Moraes
Pathogenic mitochondrial DNA (mtDNA) mutations often co-exist with wild-type molecules (mtDNA heteroplasmy). Phenotypes manifest when the percentage of mutant mtDNA is high (70-90%). Previously, our laboratory showed that mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) can eliminate mutant mtDNA from heteroplasmic cells. However, mitoTALENs are dimeric and relatively large, making it difficult to package their coding genes into viral vectors, limiting their clinical application...
July 16, 2018: EMBO Molecular Medicine
Daniel Muñoz-Espín, Miguel Rovira, Irene Galiana, Cristina Giménez, Beatriz Lozano-Torres, Marta Paez-Ribes, Susana Llanos, Selim Chaib, Maribel Muñoz-Martín, Alvaro C Ucero, Guillermo Garaulet, Francisca Mulero, Stephen G Dann, Todd VanArsdale, David J Shields, Andrea Bernardos, José Ramón Murguía, Ramón Martínez-Máñez, Manuel Serrano
Senescent cells accumulate in multiple aging-associated diseases, and eliminating these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high lysosomal β-galactosidase activity of senescent cells to design a drug delivery system based on the encapsulation of drugs with galacto-oligosaccharides. We show that gal-encapsulated fluorophores are preferentially released within senescent cells in mice. In a model of chemotherapy-induced senescence, gal-encapsulated cytotoxic drugs target senescent tumor cells and improve tumor xenograft regression in combination with palbociclib...
July 16, 2018: EMBO Molecular Medicine
Romina Durigon, Alice L Mitchell, Aleck We Jones, Andreea Manole, Mara Mennuni, Elizabeth Ma Hirst, Henry Houlden, Giuseppe Maragni, Serena Lattante, Paolo Niccolo' Doronzio, Ilaria Dalla Rosa, Marcella Zollino, Ian J Holt, Antonella Spinazzola
The diverse clinical phenotypes of Wolf-Hirschhorn syndrome (WHS) are the result of haploinsufficiency of several genes, one of which, LETM1 , encodes a protein of the mitochondrial inner membrane of uncertain function. Here, we show that LETM1 is associated with mitochondrial ribosomes, is required for mitochondrial DNA distribution and expression, and regulates the activity of an ancillary metabolic enzyme, pyruvate dehydrogenase. LETM1 deficiency in WHS alters mitochondrial morphology and DNA organization, as does substituting ketone bodies for glucose in control cells...
July 16, 2018: EMBO Molecular Medicine
Pablo Ranea-Robles, Nathalie Launay, Montserrat Ruiz, Noel Ylagan Calingasan, Magali Dumont, Alba Naudí, Manuel Portero-Otín, Reinald Pamplona, Isidre Ferrer, M Flint Beal, Stéphane Fourcade, Aurora Pujol
The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model ( Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3β...
July 11, 2018: EMBO Molecular Medicine
Lise Van Wyngene, Jolien Vandewalle, Claude Libert
Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside...
July 5, 2018: EMBO Molecular Medicine
Irem Bayindir-Buchhalter, Gretchen Wolff, Sarah Lerch, Tjeerd Sijmonsma, Maximilian Schuster, Jan Gronych, Adrian T Billeter, Rohollah Babaei, Damir Krunic, Lars Ketscher, Nadine Spielmann, Martin Hrabe de Angelis, Jorge L Ruas, Beat P Müller-Stich, Mathias Heikenwalder, Peter Lichter, Stephan Herzig, Alexandros Vegiopoulos
Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context-specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone-dependent transcriptional program...
July 4, 2018: EMBO Molecular Medicine
Alazne Zabala, Nuria Vazquez-Villoldo, Björn Rissiek, Jon Gejo, Abraham Martin, Aitor Palomino, Alberto Perez-Samartín, Krishna R Pulagam, Marco Lukowiak, Estibaliz Capetillo-Zarate, Jordi Llop, Tim Magnus, Friedrich Koch-Nolte, Francois Rassendren, Carlos Matute, María Domercq
Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen- or tissue damage-induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative responses. Here, we analyzed the role of purinergic receptor P2X4 (P2X4R) in microglia/macrophages during autoimmune inflammation. Blockade of P2X4R signaling exacerbated clinical signs in the experimental autoimmune encephalomyelitis (EAE) model and also favored microglia activation to a pro-inflammatory phenotype and inhibited myelin phagocytosis...
July 4, 2018: EMBO Molecular Medicine
Ming Zhao, Xiwen Xiong, Kaiqun Ren, Bing Xu, Meng Cheng, Chinmayi Sahu, Kaichun Wu, Yongzan Nie, Zan Huang, Richard S Blumberg, Xiaonan Han, Hai-Bin Ruan
Post-translational modifications in intestinal epithelial cells (IECs) allow for precise control in intestinal homeostasis, the breakdown of which may precipitate the pathological damage and inflammation in inflammatory bowel disease. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification on intracellular proteins controls diverse biological processes; however, its roles in intestinal homeostasis are still largely unexplored. Here, we found that levels of protein O-GlcNAcylation and the expression of O-GlcNAc transferase (OGT), the enzyme adding the O-GlcNAc moiety, were reduced in IECs in human IBD patients...
June 25, 2018: EMBO Molecular Medicine
Andrea Resovi, Maria Rosa Bani, Luca Porcu, Alessia Anastasia, Lucia Minoli, Paola Allavena, Paola Cappello, Francesco Novelli, Aldo Scarpa, Eugenio Morandi, Anna Falanga, Valter Torri, Giulia Taraboletti, Dorina Belotti, Raffaella Giavazzi
The clinical management of pancreatic ductal adenocarcinoma (PDAC) is hampered by the lack of reliable biomarkers. This study investigated the value of soluble stroma-related molecules as PDAC biomarkers. In the first exploratory phase, 12 out of 38 molecules were associated with PDAC in a cohort of 25 PDAC patients and 16 healthy subjects. A second confirmatory phase on an independent cohort of 131 PDAC patients, 30 chronic pancreatitis patients, and 131 healthy subjects confirmed the PDAC association for MMP7, CCN2, IGFBP2, TSP2, sICAM1, TIMP1, and PLG Multivariable logistic regression model identified biomarker panels discriminating respectively PDAC versus healthy subjects (MMP7 + CA19...
June 25, 2018: EMBO Molecular Medicine
Daniel E Foxler, Katherine S Bridge, John G Foster, Paul Grevitt, Sean Curry, Kunal M Shah, Kathryn M Davidson, Ai Nagano, Emanuela Gadaleta, Hefin I Rhys, Paul T Kennedy, Miguel A Hermida, Ting-Yu Chang, Peter E Shaw, Louise E Reynolds, Tristan R McKay, Hsei-Wei Wang, Paulo S Ribeiro, Michael J Plevin, Dimitris Lagos, Nicholas R Lemoine, Prabhakar Rajan, Trevor A Graham, Claude Chelala, Kairbaan M Hodivala-Dilke, Ian Spendlove, Tyson V Sharp
The adaptive cellular response to low oxygen tensions is mediated by the hypoxia-inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF-α and HIF-β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumorigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour-suppressive mechanism. LIMD1 complexes with PHD2 and VHL in physiological oxygen levels (normoxia) to facilitate proteasomal degradation of the HIF-α subunit...
June 21, 2018: EMBO Molecular Medicine
Francesco Di Virgilio, Alba Clara Sarti
No abstract text is available yet for this article.
August 2018: EMBO Molecular Medicine
Carlos Henrique Sponton, Shingo Kajimura
No abstract text is available yet for this article.
August 2018: EMBO Molecular Medicine
Veronica Jimenez, Claudia Jambrina, Estefania Casana, Victor Sacristan, Sergio Muñoz, Sara Darriba, Jordi Rodó, Cristina Mallol, Miquel Garcia, Xavier León, Sara Marcó, Albert Ribera, Ivet Elias, Alba Casellas, Ignasi Grass, Gemma Elias, Tura Ferré, Sandra Motas, Sylvie Franckhauser, Francisca Mulero, Marc Navarro, Virginia Haurigot, Jesus Ruberte, Fatima Bosch
Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21...
August 2018: EMBO Molecular Medicine
Sachie Hiratsuka, Takeshi Tomita, Taishi Mishima, Yuta Matsunaga, Tsutomu Omori, Sachie Ishibashi, Satoshi Yamaguchi, Tsuyoshi Hosogane, Hiroshi Watarai, Miyuki Omori-Miyake, Tomoko Yamamoto, Noriyuki Shibata, Akira Watanabe, Hiroyuki Aburatani, Michio Tomura, Katherine A High, Yoshiro Maru
Primary tumours establish metastases by interfering with distinct organs. In pre-metastatic organs, a tumour-friendly microenvironment supports metastatic cells and is prepared by many factors including tissue resident cells, bone marrow-derived cells and abundant fibrinogen depositions. However, other components are unclear. Here, we show that a third organ, originally regarded as a bystander, plays an important role in metastasis by directly affecting the pre-metastatic soil. In our model system, the liver participated in lung metastasis as a leucocyte supplier...
July 2018: EMBO Molecular Medicine
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...
July 2018: EMBO Molecular Medicine
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