mRNA mediates passive vaccination against infectious agents, toxins, and tumors
In conclusion, the present study demonstrates the utility of formulated mRNA as a potent novel technology for passive immunization.
As a transient carrier of information, exogenous mRNA is considered a possibly powerful tool to instruct a body to produce its own therapeutics. Antibody‐encoding, sequence‐optimized but otherwise unmodified mRNA in LNPs empowered mice to successfully fight various biological threats. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Moritz Thran, Jean Mukherjee, Marion P önisch, Katja Fiedler, Andreas Thess, Barbara L Mui, Michael J Hope, Ying K Tam, Nigel Horscroft, Regina Heidenreich, Mariola Fotin‐Mleczek, Charles B Shoemaker, Thomas Schlake Tags: Research Article Source Type: research
CDK6 protects epithelial ovarian cancer from platinum ‐induced death via FOXO3 regulation
Abstract
Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum‐based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by...
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Alessandra Dall'Acqua, Maura Sonego, Ilenia Pellizzari, Ilenia Pellarin, Vincenzo Canzonieri, Sara D'Andrea, Sara Benevol, Roberto Sorio, Giorgio Giorda, Daniela Califano, Marina Bagnoli, Loredana Militello, Delia Mezzanzanica, Gennaro Chiappetta, Joshua Tags: Research Article Source Type: research
β‐Klotho sustains postnatal GnRH biology and spins the thread of puberty
This article highlights the newly discovered role of β‐Klotho in postnatal GnRH biology through the identification of a patient congenital hypogonadotropic hypogonadism‐associated FGFR1 mutation that results in decreased FGF21 metabolic signaling. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Micheline Misrahi Tags: News & Views Source Type: research
The cardiac microenvironment uses non ‐canonical WNT signaling to activate monocytes after myocardial infarction
This study investigated microenvironment‐dependent changes in inflammatory monocytes after MI. RNA sequencing analysis of murine Ly6Chigh monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes—but not fibroblasts or endothelial cells—upon hypoxia. Compared to wild‐type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fr...
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Ingmar S ören Meyer, Andreas Jungmann, Christoph Dieterich, Min Zhang, Felix Lasitschka, Susann Werkmeister, Jan Haas, Oliver J Müller, Michael Boutros, Matthias Nahrendorf, Hugo A Katus, Stefan E Hardt, Florian Leuschner Tags: Research Article Source Type: research
Clinical development of CAR T cells —challenges and opportunities in translating innovative treatment concepts
Abstract
Chimeric antigen receptor (CAR) T cell therapy, together with checkpoint inhibition, has been celebrated as a breakthrough technology due to the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B‐cell malignancies. In this review, we provide a comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti‐tumor activities, and related toxicities. More than 200 CAR T cell clinical trials have been initiated so far, most of which aim to ...
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Jessica Hartmann, Martina Sch üßler‐Lenz, Attilio Bondanza, Christian J Buchholz Tags: Review Source Type: research
Going viral? Linking the etiology of human prostate cancer to the PCA3 long noncoding RNA and oncogenic viruses
The hypothesis is discussed that prostate cancer marker lncRNA PCA3 was introduced into the human genome by an oncogenic virus, and that viral infection‐related mechanisms might underlie its overexpression and prostate cancer initiation and/or progression. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - July 27, 2017 Category: Molecular Biology Authors: Andre A Teixeira, Serena Marchi ò, Emmanuel Dias‐Neto, Diana N Nunes, Israel T da Silva, Bryce Chackerian, Marc Barry, Richard C Lauer, Ricardo J Giordano, Richard L Sidman, Cosette M Wheeler, Webster K Cavenee, Renata Pasqualini, Wadih Arap Tags: Opinion Source Type: research
Promoterless gene targeting without nucleases rescues lethality of a Crigler ‐Najjar syndrome mouse model
Abstract
Crigler‐Najjar syndrome type I (CNSI) is a rare monogenic disease characterized by severe neonatal unconjugated hyperbilirubinemia with a lifelong risk of neurological damage and death. Liver transplantation is the only curative option, which has several limitations and risks. We applied an in vivo gene targeting approach based on the insertion, without the use of nucleases, of a promoterless therapeutic cDNA into the albumin locus of a mouse model reproducing all major features of CNSI. Neonatal transduction with the donor vector resulted in the complete rescue from neonatal lethality, with a therapeutic reduc...
Source: EMBO Molecular Medicine - July 27, 2017 Category: Molecular Biology Authors: Fabiola Porro, Giulia Bortolussi, Adi Barzel, Alessia De Caneva, Alessandra Iaconcig, Simone Vodret, Lorena Zentilin, Mark A Kay, Andr és F Muro Tags: Report Source Type: research
18F ‐AV‐1451 and CSF T‐tau and P‐tau as biomarkers in Alzheimer's disease
Abstract
To elucidate the relationship between cerebrospinal fluid (CSF) total‐tau (T‐tau) and phosphorylated tau (P‐tau) with the tau PET ligand 18F‐AV‐1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T‐tau and P‐tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F‐AV‐1451, and mainly in demented AD patients. 18F‐AV‐1451, but not CSF T‐tau or P‐tau, was strongly associated with atrophy and cognitive impairment. CSF tau was incre...
Source: EMBO Molecular Medicine - July 25, 2017 Category: Molecular Biology Authors: Niklas Mattsson, Michael Sch öll, Olof Strandberg, Ruben Smith, Sebastian Palmqvist, Philip S Insel, Douglas Hägerström, Tomas Ohlsson, Henrik Zetterberg, Jonas Jögi, Kaj Blennow, Oskar Hansson Tags: Research Article Source Type: research
Rethinking the nonprofit foundation: an emerging niche in the rare disease ecosystem
In recent years, medical foundations have become increasingly influential, and now play an instrumental and integral role in the research and development of their disease area of interest. While some foundations have directly invested in taking drug candidates to the clinic, others have focused on creating specific tools for accelerating the identification and development of effective treatments. Here, we describe a new model, developed by the Children's Tumor Foundation (CTF), by which foundations may play a role in the rare disease ecosystem. On the one hand, the CTF uses its position to build bridges between academic sc...
Source: EMBO Molecular Medicine - July 25, 2017 Category: Molecular Biology Authors: Annette C Bakker, Salvatore La Rosa Tags: Commentary Source Type: research
Phenotypic diversity drives paracrine drug tolerance
Considerable clinical successes have been achieved in cancer treatment since the introduction of targeted therapies. However, almost inevitably tumors develop therapy resistance, which limits durable clinical responses. Tumors are often heterogeneous, and as a result, therapy‐resistant cells are present even before the start of treatment. Resistance is commonly mediated via genetic changes. However, in this issue of EMBO Molecular Medicine, Smith et al () report that phenotypic heterogeneity can contribute to resistance as well.
Kuilman and Peeper discuss the findings by Smith, Wellbrock et al showing that during BRAF...
Source: EMBO Molecular Medicine - July 10, 2017 Category: Molecular Biology Authors: Thomas Kuilman, Daniel S Peeper Tags: News & Views Source Type: research
MG132 ‐induced progerin clearance is mediated by autophagy activation and splicing regulation
Abstract
Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A‐type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautoph...
Source: EMBO Molecular Medicine - July 3, 2017 Category: Molecular Biology Authors: Karim Harhouri, Claire Navarro, Danielle Depetris, Marie ‐Geneviève Mattei, Xavier Nissan, Pierre Cau, Annachiara De Sandre‐Giovannoli, Nicolas Lévy Tags: Research Article Source Type: research
KLB, encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism
Abstract
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening o...
Source: EMBO Molecular Medicine - July 1, 2017 Category: Molecular Biology Authors: Cheng Xu, Andrea Messina, Emmanuel Somm, Hichem Miraoui, Tarja Kinnunen, James Acierno, Nicolas J Niederl änder, Justine Bouilly, Andrew A Dwyer, Yisrael Sidis, Daniele Cassatella, Gerasimos P Sykiotis, Richard Quinton, Christian De Geyter, Mirjam Dirlew Tags: Research Article Source Type: research
Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis
Abstract
The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine‐metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the levels of intracellular adenosine in human endothelial cells. Knockdown (KD) of ADK elevated intracellular adenosine, promoted proliferation, migration, and angiogenic sprouting in human endothelial cells. Additionally, mice deficient in endothelial ADK displayed increased angiogenesis as evidenced ...
Source: EMBO Molecular Medicine - July 1, 2017 Category: Molecular Biology Authors: Yiming Xu, Yong Wang, Siyuan Yan, Yaqi Zhou, Qiuhua Yang, Yue Pan, Xianqiu Zeng, Xiaofei An, Zhiping Liu, Lina Wang, Jiean Xu, Yapeng Cao, David J Fulton, Neal L Weintraub, Zsolt Bagi, Md Nasrul Hoda, Xiaoling Wang, Qinkai Li, Mei Hong, Xuejun Jiang, Detl Tags: Research Article Source Type: research
Spironolactone is an antagonist of NRG1 ‐ERBB4 signaling and schizophrenia‐relevant endophenotypes in mice
Abstract
Enhanced NRG1‐ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway‐directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell‐based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1‐ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to ass...
Source: EMBO Molecular Medicine - July 1, 2017 Category: Molecular Biology Authors: Michael C Wehr, Wilko Hinrichs, Magdalena M Brz ózka, Tilmann Unterbarnscheidt, Alexander Herholt, Jan P Wintgens, Sergi Papiol, Maria Clara Soto‐Bernardini, Mykola Kravchenko, Mingyue Zhang, Klaus‐Armin Nave, Sven P Wichert, Peter Falkai, Weiqi Zhan Tags: Research Article Source Type: research
BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity
Abstract
Maintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR‐compromised cells are sensitive to acetaldehyde, similarly to FANCD2‐deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDH...
Source: EMBO Molecular Medicine - July 1, 2017 Category: Molecular Biology Authors: Eliana MC Tacconi, Xianning Lai, Cecilia Folio, Manuela Porru, Gijs Zonderland, Sophie Badie, Johanna Michl, Irene Sechi, M élanie Rogier, Verónica Matía García, Ankita Sati Batra, Oscar M Rueda, Peter Bouwman, Jos Jonkers, Anderson Ryan, Bernardo Rei Tags: Research Article Source Type: research
