Compounds producing an effective combinatorial regimen for disruption of HIV ‐1 latency
This study reveals new compounds that reverse HIV‐1 latency, demonstrated through in vitro and ex vivo investigation. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: Pargol Hashemi, Kris Barreto, Wendy Bernhard, Adam Lomness, Nicolette Honson, Tom A Pfeifer, P Richard Harrigan, Ivan Sadowski Tags: Research Article Source Type: research
Reversible immortalisation enables genetic correction of human muscle progenitors and engineering of next ‐generation human artificial chromosomes for Duchenne muscular dystrophy
Abstract
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 locu...
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: 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 Nald Tags: Research Article Source Type: research
The chemokine receptor CX3CR1 coordinates monocyte recruitment and endothelial regeneration after arterial injury
Abstract
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. In Cx3cr1‐deficient mice recruitment of Ly6Clo monocytes, endothel...
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: Tobias Getzin, Kashyap Krishnasamy, Jaba Gamrekelashvili, Tamar Kapanadze, Anne Limbourg, Christine H äger, L Christian Napp, Johann Bauersachs, Hermann Haller, Florian P Limbourg Tags: Report Source Type: research
FoxO3 an important player in fibrogenesis and therapeutic target for idiopathic pulmonary fibrosis
Abstract
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 ...
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: 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 Tags: Research Article Source Type: research
An oligoclonal antibody durably overcomes resistance of lung cancer to third ‐generation EGFR inhibitors
Abstract
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. We now report that 3×mAbs, including a triplet containing...
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: Maicol Mancini, Hilah Gal, Nad ège 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 Tags: Research Article Source Type: research
The diphenylpyrazole compound anle138b blocks A β channels and rescues disease phenotypes in a mouse model for amyloid pathology
In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD‐related pathology that should be investigated further.
Although a substantial amount of data point to a causative role of amyloid beta and Tau pathology in Alzheimer's disease (AD) pathogenesis, no effective therapy has been developed. This study reports that anle138b blocks amyloid beta channels formation and ameliorates disease pathology. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: 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, Mar Tags: Research Article Source Type: research
Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy
(Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: Borislav Dejanovic, Tania Dj émié, Nora Grünewald, Arvid Suls, Vanessa Kress, Florian Hetsch, Dana Craiu, Matthew Zemel, Padhraig Gormley, Dennis Lal, , Candace T Myers, Heather C Mefford, Aarno Palotie, Ingo Helbig, Jochen C Meier, Peter De Jonghe, Sa Tags: Corrigendum Source Type: research
Peroxisome proliferator ‐activated receptor gamma (PPARγ) is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target
(Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: Oren Pleniceanu, Racheli Shukrun, Dorit Omer, Einav Vax, Itamar Kanter, Klaudyna Dziedzic, Naomi Pode ‐Shakked, Michal Mark‐Daniei, Sara Pri‐Chen, Yehudit Gnatek, Hadas Alfandary, Nira Varda‐Bloom, Dekel D Bar‐Lev, Naomi Bollag, Rachel Shtainfel Tags: Corrigendum Source Type: research
CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival
We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyndromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2−/− mice display an early onset profound deafness and have normal balance and retinal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2−/− mice, unlike those of mice defective for the other five known USH1 proteins, begin only after ...
Source: EMBO Molecular Medicine - December 1, 2017 Category: Molecular Biology Authors: Vincent Michel, Kevin T Booth, Pranav Patni, Matteo Cortese, Hela Azaiez, Amel Bahloul, Kimia Kahrizi, M énélik Labbé, Alice Emptoz, Andrea Lelli, Julie Dégardin, Typhaine Dupont, Asadollah Aghaie, Danuta Oficjalska‐Pham, Serge Picaud, Hossein Najma Tags: Research Article Source Type: research
Thrombopoietin: tickling the HSC's fancy
This report also refines our understanding of the role of THPO in human HSC function and illustrates the important biological insight that can be gained through studies of such rare genetic disorders.
Kim and Sankaram discuss the finding by Pecci, Savoia et al showing that congenital amegakaryocytic thrombocytopenia (CAMT) caused by a novel missense mutation in the thrombopoietin (THPO) gene, can be cured with the THPO‐mimetic romiplostim. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - November 30, 2017 Category: Molecular Biology Authors: Ah Ram Kim, Vijay G Sankaran Tags: News & Views Source Type: research
Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with romiplostim
Abstract
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.R119C affects not only ability of the cytokine to stimulate MPL but also its...
Source: EMBO Molecular Medicine - November 30, 2017 Category: Molecular Biology Authors: 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 Tags: Research Article Source Type: research
Patients with rare diseases: from therapeutic orphans to pioneers of personalized treatments
Common diseases, such as cancer, diabetes mellitus, or Alzheimer's disease, affect a large segment of the population, which justifies the enormous financial allocations for translational and clinical research. In contrast, the ~5,000 known rare disorders affect only very few patients each, even though the cumulative disease burden is substantial. This influences not only the general appreciation of research to address rare diseases, but also the allocation of research funds. Importantly, however, studying rare diseases has contributed enormously to our understanding of human biochemistry, cell and developmental biology, an...
Source: EMBO Molecular Medicine - November 27, 2017 Category: Molecular Biology Authors: Christoph Klein, William A Gahl Tags: Commentary Source Type: research
SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis
In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis.
The exten...
Source: EMBO Molecular Medicine - November 6, 2017 Category: Molecular Biology Authors: Varinder S Athwal, James Pritchett, Jessica Llewellyn, Katherine Martin, Elizabeth Camacho, Sayyid MA Raza, Alexander Phythian ‐Adams, Lindsay J Birchall, Aoibheann F Mullan, Kim Su, Laurence Pearmain, Grace Dolman, Abed M Zaitoun, Scott L Friedman, And Tags: Research Article Source Type: research
A proteomic network approach across the ALS ‐FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain
Abstract
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 ...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: 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 Tags: Research Article Source Type: research
Ceruloplasmin replacement therapy ameliorates neurological symptoms in a preclinical model of aceruloplasminemia
Abstract
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 cerulo...
Source: EMBO Molecular Medicine - November 1, 2017 Category: Molecular Biology Authors: Alan Zanardi, Antonio Conti, Marco Cremonesi, Patrizia D'Adamo, Enrica Gilberti, Pietro Apostoli, Carlo Vittorio Cannistraci, Alberto Piperno, Samuel David, Massimo Alessio Tags: Research Article Source Type: research
