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Sleeping beauty transposon

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https://www.readbyqxmd.com/read/27913727/regulated-complex-assembly-safeguards-the-fidelity-of-sleeping-beauty-transposition
#1
Yongming Wang, Diana Pryputniewicz-Dobrinska, Enikö Éva Nagy, Christopher D Kaufman, Manvendra Singh, Steve Yant, Jichang Wang, Anna Dalda, Mark A Kay, Zoltán Ivics, Zsuzsanna Izsvák
The functional relevance of the inverted repeat structure (IR/DR) in a subgroup of the Tc1/mariner superfamily of transposons has been enigmatic. In contrast to mariner transposition, where a topological filter suppresses single-ended reactions, the IR/DR orchestrates a regulatory mechanism to enforce synapsis of the transposon ends before cleavage by the transposase occurs. This ordered assembly process shepherds primary transposase binding to the inner 12DRs (where cleavage does not occur), followed by capture of the 12DR of the other transposon end...
December 1, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27898092/transposon-mediated-generation-of-cellular-and-mouse-models-of-splicing-mutations-to-assess-the-efficacy-of-snrna-based-therapeutics
#2
Elena Barbon, Mattia Ferrarese, Laetitia van Wittenberghe, Peggy Sanatine, Giuseppe Ronzitti, Fanny Collaud, Pasqualina Colella, Mirko Pinotti, Federico Mingozzi
Disease-causing splicing mutations can be rescued by variants of the U1 small nuclear RNA (U1snRNAs). However, the evaluation of the efficacy and safety of modified U1snRNAs as therapeutic tools is limited by the availability of cellular and animal models specific for a given mutation. Hence, we exploited the hyperactive Sleeping Beauty transposon system (SB100X) to integrate human factor IX (hFIX) minigenes into genomic DNA in vitro and in vivo. We generated stable HEK293 cell lines and C57BL/6 mice harboring splicing-competent hFIX minigenes either wild type (SChFIX-wt) or mutated (SChFIXex5-2C)...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27832434/monitoring-of-venus-transgenic-cell-migration-during-pregnancy-in-non-transgenic-rabbits
#3
N Lipták, O I Hoffmann, A Kerekes, G Iski, D Ernszt, K Kvell, L Hiripi, Z Bősze
Cell transfer between mother and fetus were demonstrated previously in several species which possess haemochorial placenta (e.g. in humans, mice, rats, etc.). Here we report the assessment of fetal and maternal microchimerism in non-transgenic (non-TG) New Zealand white rabbits which were pregnant with transgenic (TG) fetuses and in non-TG newborns of TG does. The TG construct, including the Venus fluorophore cDNA driven by a ubiquitous cytomegalovirus enhancer, chicken ß-actin promoter (CAGGS), was previously integrated into the rabbit genome by Sleeping Beauty transposon system...
November 10, 2016: Transgenic Research
https://www.readbyqxmd.com/read/27801667/transposon-mediated-generation-of-bcr-abl1-expressing-transgenic-cell-lines-for-unbiased-sensitivity-testing-of-tyrosine-kinase-inhibitors
#4
Konstantin Byrgazov, Chantal Blanche Lucini, Bettina Berkowitsch, Margit Koenig, Oskar A Haas, Gregor Hoermann, Peter Valent, Thomas Lion
Point mutations in the ABL1 kinase domain are an important mechanism of resistance to tyrosine kinase inhibitors (TKI) in BCR-ABL1-positive and, as recently shown, BCR-ABL1-like leukemias. The cell line Ba/F3 lentivirally transduced with mutant BCR-ABL1 constructs is widely used for in vitro sensitivity testing and response prediction to tyrosine kinase inhibitors. The transposon-based Sleeping Beauty system presented offers several advantages over lentiviral transduction including the absence of biosafety issues, faster generation of transgenic cell lines, and greater efficacy in introducing large gene constructs...
October 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27790711/transposon-mutagenesis-identifies-candidate-genes-that-cooperate-with-loss-of-transforming-growth-factor-beta-signaling-in-mouse-intestinal-neoplasms
#5
Shelli M Morris, Jerry Davison, Kelly T Carter, Rachele M O'Leary, Patty Trobridge, Sue E Knoblaugh, Lois L Myeroff, Sanford D Markowitz, Benjamin T Brett, Todd E Scheetz, Adam J Dupuy, Timothy K Starr, William M Grady
Colorectal cancer (CRC) results from the accumulation of gene mutations and epigenetic alterations in colon epithelial cells, which promotes CRC formation through deregulating signaling pathways. One of the most commonly deregulated signaling pathways in CRC is the transforming growth factor β (TGF-β) pathway. Importantly, the effects of TGF-β signaling inactivation in CRC are modified by concurrent mutations in the tumor cell, and these concurrent mutations determine the ultimate biological effects of impaired TGF-β signaling in the tumor...
October 28, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27729044/retroviral-vectors-and-transposons-for-stable-gene-therapy-advances-current-challenges-and-perspectives
#6
José Eduardo Vargas, Leonardo Chicaybam, Renato Tetelbom Stein, Amilcar Tanuri, Andrés Delgado-Cañedo, Martin H Bonamino
Gene therapy protocols require robust and long-term gene expression. For two decades, retrovirus family vectors have offered several attractive properties as stable gene-delivery vehicles. These vectors represent a technology with widespread use in basic biology and translational studies that require persistent gene expression for treatment of several monogenic diseases. Immunogenicity and insertional mutagenesis represent the main obstacles to a wider clinical use of these vectors. Efficient and safe non-viral vectors are emerging as a promising alternative and facilitate clinical gene therapy studies...
October 12, 2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27696897/sleeping-beauty-transposition-from-biology-to-applications
#7
Suneel A Narayanavari, Shreevathsa S Chilkunda, Zoltán Ivics, Zsuzsanna Izsvák
Sleeping Beauty (SB) is the first synthetic DNA transposon that was shown to be active in a wide variety of species. Here, we review studies from the last two decades addressing both basic biology and applications of this transposon. We discuss how host-transposon interaction modulates transposition at different steps of the transposition reaction. We also discuss how the transposon was translated for gene delivery and gene discovery purposes. We critically review the system in clinical, pre-clinical and non-clinical settings as a non-viral gene delivery tool in comparison with viral technologies...
October 4, 2016: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27574698/transcriptionally-regulated-and-nontoxic-delivery-of-the-hyperactive-sleeping-beauty-transposase
#8
Fabienne Cocchiarella, Maria Carmela Latella, Valentina Basile, Francesca Miselli, Melanie Galla, Carol Imbriano, Alessandra Recchia
The Sleeping Beauty (SB) transposase and, in particular, its hyperactive variant SB100X raises increasing interest for gene therapy application, including genome modification and, more recently, induced pluripotent stem cells (iPS) reprogramming. The documented cytotoxicity of the transposase, when constitutively expressed by an integrating retroviral vector (iRV), has been circumvented by the transient delivery of SB100X using retroviral mRNA transfer. In this study, we developed an alternative, safe, and efficient transposase delivery system based on a tetracycline-ON regulated expression cassette and the rtTA2(S)-M2 transactivator gene transiently delivered by integration-defective lentiviral vectors (IDLVs)...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/27491640/enhanced-car-t-cell-engineering-using-non-viral-sleeping-beauty-transposition-from-minicircle-vectors
#9
R Monjezi, C Miskey, T Gogishvili, M Schleef, M Schmeer, H Einsele, Z Ivics, M Hudecek
Immunotherapy with T cell modified with gamma-retroviral or lentiviral (LV) vectors to express a chimeric antigen receptor (CAR) has shown remarkable efficacy in clinical trials. However, the potential for insertional mutagenesis and genotoxicity of viral vectors is a safety concern, and their cost and regulatory demands a roadblock for rapid and broad clinical translation. Here, we demonstrate that CAR T cells can be engineered through non-viral Sleeping Beauty (SB) transposition of CAR genes from minimalistic DNA vectors called minicircles (MCs)...
August 5, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27479497/analyzing-tumor-heterogeneity-and-driver-genes-in-single-myeloid-leukemia-cells-with-sbcapseq
#10
Karen M Mann, Justin Y Newberg, Michael A Black, Devin J Jones, Felipe Amaya-Manzanares, Liliana Guzman-Rojas, Takahiro Kodama, Jerrold M Ward, Alistair G Rust, Louise van der Weyden, Christopher Chin Kuan Yew, Jill L Waters, Marco L Leung, Keith Rogers, Susan M Rogers, Leslie A McNoe, Luxmanan Selvanesan, Nicholas Navin, Nancy A Jenkins, Neal G Copeland, Michael B Mann
A central challenge in oncology is how to kill tumors containing heterogeneous cell populations defined by different combinations of mutated genes. Identifying these mutated genes and understanding how they cooperate requires single-cell analysis, but current single-cell analytic methods, such as PCR-based strategies or whole-exome sequencing, are biased, lack sequencing depth or are cost prohibitive. Transposon-based mutagenesis allows the identification of early cancer drivers, but current sequencing methods have limitations that prevent single-cell analysis...
September 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/27451971/hepatic-overexpression-of-hemopexin-inhibits-inflammation-and-vascular-stasis-in-murine-models-of-sickle-cell-disease
#11
Gregory M Vercellotti, Ping Zhang, Julia Nguyen, Fuad Abdulla, Chunsheng Chen, Phong Nguyen, Carlos Nowotny, Clifford J Steer, Ann Smith, John D Belcher
Sickle cell disease (SCD) patients have low serum hemopexin (Hpx) levels due to chronic hemolysis. We hypothesize that in SCD mice, hepatic overexpression of hemopexin will scavenge the proximal mediator of vascular activation, heme, and will inhibit inflammation and microvascular stasis. To examine the protective role of Hpx in SCD, we transplanted bone marrow from NY1DD SCD mice into Hpx(-/-) or Hpx(+/+) C57BL/6 mice. Dorsal skin fold chambers were implanted in week 13 post-transplant and microvascular stasis (% non-flowing venules) evaluated in response to heme infusion...
July 19, 2016: Molecular Medicine
https://www.readbyqxmd.com/read/27434682/a-high-capacity-adenoviral-hybrid-vector-system-utilizing-the-hyperactive-sleeping-beauty-transposase-sb100x-for-enhanced-integration
#12
Philip Boehme, Wenli Zhang, Manish Solanki, Eric Ehrke-Schulz, Anja Ehrhardt
For efficient delivery of required genetic elements we utilized high-capacity adenoviral vectors in the past allowing high transgene capacities of up to 36 kb. Previously we explored the hyperactive Sleeping Beauty (SB) transposase (HSB5) for somatic integration from the high-capacity adenoviral vectors genome. To further improve this hybrid vector system we hypothesized that the previously described hyperactive SB transposase SB100X will result in significantly improved efficacies after transduction of target cells...
2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27398792/a-recellularized-human-colon-model-identifies-cancer-driver-genes
#13
Huanhuan Joyce Chen, Zhubo Wei, Jian Sun, Asmita Bhattacharya, David J Savage, Rita Serda, Yuri Mackeyev, Steven A Curley, Pengcheng Bu, Lihua Wang, Shuibing Chen, Leona Cohen-Gould, Emina Huang, Xiling Shen, Steven M Lipkin, Neal G Copeland, Nancy A Jenkins, Michael L Shuler
Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia...
August 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/27389402/targeted-delivery-of-nerve-growth-factor-to-the-cholinergic-basal-forebrain-of-alzheimer-s-disease-patients-application-of-a-second-generation-encapsulated-cell-biodelivery-device
#14
Helga Eyjolfsdottir, Maria Eriksdotter, Bengt Linderoth, Göran Lind, Bengt Juliusson, Philip Kusk, Ove Almkvist, Niels Andreasen, Kaj Blennow, Daniel Ferreira, Eric Westman, Inger Nennesmo, Azadeh Karami, Taher Darreh-Shori, Ahmadul Kadir, Agneta Nordberg, Erik Sundström, Lars-Olof Wahlund, Anders Wall, Maria Wiberg, Bengt Winblad, Åke Seiger, Lars Wahlberg, Per Almqvist
BACKGROUND: Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion. METHODS: Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration...
July 7, 2016: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/27345990/generation-of-human-induced-pluripotent-stem-cell-line-from-a-patient-with-a-long-qt-syndrome-type-2
#15
Azra Fatima, Dina Ivanyuk, Stefan Herms, Stefanie Heilmann-Heimbach, Orla O'Shea, Charlotte Chapman, Zsuszanna Izsvák, Martin Farr, Jürgen Hescheler, Tomo Šarić
We report here the generation of human iPS cell line UKKi009-A from dermal fibroblasts of a patient carrying heterozygous mutation c.3035-3045delTCCCTCGATGC, p.Leu1012Pro (fs*55) in KCNH2 gene leading to long QT syndrome type 2 (LQT2). We used the Sleeping Beauty transposon-based plasmids expressing OSKM along with microRNAs 307/367 to reprogram the fibroblasts. The iPS cells possess pluripotent stem cell characteristics and differentiate to cell lineages of all three germ layers. This cell line can serve as a source for in vitro modeling of LQT2...
March 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27329815/detection-of-sleeping-beauty-transposition-in-the-genome-of-host-cells-by-non-radioactive-southern-blot-analysis
#16
Rajagopal N Aravalli, Chang W Park, Clifford J Steer
The Sleeping Beauty transposon (SB-Tn) system is being used widely as a DNA vector for the delivery of therapeutic transgenes, as well as a tool for the insertional mutagenesis in animal models. In order to accurately assess the insertional potential and properties related to the integration of SB it is essential to determine the copy number of SB-Tn in the host genome. Recently developed SB100X transposase has demonstrated an integration rate that was much higher than the original SB10 and that of other versions of hyperactive SB transposases, such as HSB3 or HSB17...
August 26, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27324781/efficient-generation-of-transgenic-cattle-using-the-dna-transposon-and-their-analysis-by-next-generation-sequencing
#17
Soo-Young Yum, Song-Jeon Lee, Hyun-Min Kim, Woo-Jae Choi, Ji-Hyun Park, Won-Wu Lee, Hee-Soo Kim, Hyeong-Jong Kim, Seong-Hun Bae, Je-Hyeong Lee, Joo-Yeong Moon, Ji-Hyun Lee, Choong-Il Lee, Bong-Jun Son, Sang-Hoon Song, Su-Min Ji, Seong-Jin Kim, Goo Jang
Here, we efficiently generated transgenic cattle using two transposon systems (Sleeping Beauty and Piggybac) and their genomes were analyzed by next-generation sequencing (NGS). Blastocysts derived from microinjection of DNA transposons were selected and transferred into recipient cows. Nine transgenic cattle have been generated and grown-up to date without any health issues except two. Some of them expressed strong fluorescence and the transgene in the oocytes from a superovulating one were detected by PCR and sequencing...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27323395/immunotherapy-of-acute-leukemia-by-chimeric-antigen-receptor-modified-lymphocytes-using-an-improved-sleeping-beauty-transposon-platform
#18
Chiara F Magnani, Nice Turazzi, Fabrizio Benedicenti, Andrea Calabria, Erika Tenderini, Sarah Tettamanti, Greta M P Giordano Attianese, Laurence J N Cooper, Alessandro Aiuti, Eugenio Montini, Andrea Biondi, Ettore Biagi
Chimeric antigen receptor (CAR)-modified T-cell adoptive immunotherapy is a remarkable therapeutic option proven effective in the treatment of hematological malignancies. In order to optimize cell manufacturing, we sought to develop a novel clinical-grade protocol to obtain CAR-modified cytokine-induced killer cells (CIKs) using the Sleeping Beauty (SB) transposon system. Administration of irradiated PBMCs overcame cell death of stimulating cells induced by non-viral transfection, enabling robust gene transfer together with efficient T-cell expansion...
June 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27247392/transposon-mutagenesis-identifies-genes-and-cellular-processes-driving-epithelial-mesenchymal-transition-in-hepatocellular-carcinoma
#19
Takahiro Kodama, Justin Y Newberg, Michiko Kodama, Roberto Rangel, Kosuke Yoshihara, Jean C Tien, Pamela H Parsons, Hao Wu, Milton J Finegold, Neal G Copeland, Nancy A Jenkins
Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMT-TFs)...
June 14, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27246312/imaging-of-sleeping-beauty-modified-cd19-specific-t-cells-expressing-hsv1-thymidine-kinase-by-positron-emission-tomography
#20
Amer M Najjar, Pallavi R Manuri, Simon Olivares, Leo Flores, Tiejuan Mi, Helen Huls, Elizabeth J Shpall, Richard E Champlin, Nashaat Turkman, Vincenzo Paolillo, Jason Roszik, Brian Rabinovich, Dean A Lee, Mian Alauddin, Juri Gelovani, Laurence J N Cooper
PURPOSE: We have incorporated a positron emission tomography (PET) functionality in T cells expressing a CD19-specific chimeric antigen receptor (CAR) to non-invasively monitor the adoptively transferred cells. PROCEDURES: We engineered T cells to express CD19-specific CAR, firefly luciferase (ffLuc), and herpes simplex virus type-1 thymidine kinase (TK) using the non-viral-based Sleeping Beauty (SB) transposon/transposase system adapted for human application. Electroporated primary T cells were propagated on CD19(+) artificial antigen-presenting cells...
December 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
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