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https://www.readbyqxmd.com/read/29330288/epigenetically-regulated-chromosome-14q32-mirna-cluster-induces-metastasis-and-predicts-poor-prognosis-in-lung-adenocarcinoma-patients
#1
Margarita Gonzalez-Vallinas, Manuel Rodriguez-Paredes, Marco Albrecht, Carsten Sticht, Damian Stichel, Julian Gutekunst, Adriana Pitea, Steffen Sass, Francisco J Sánchez-Rivera, Justo L Bermejo, Jennifer Schmitt, Carolina De La Torre, Arne Warth, Fabian Theis, Nikola Mueller, Norbert Gretz, Thomas Muley, Michael Meister, Darjus F Tschaharganeh, Peter Schirmacher, Franziska Matthäus, Kai Breuhahn
Most lung cancer deaths are related to metastases, which indicates the necessity of detecting and inhibiting tumor cell dissemination. Here, we aimed to identify microRNAs (miRNAs) involved in metastasis of lung adenocarcinoma as prognostic biomarkers and therapeutic targets. To that end, lymph node metastasis-associated miRNAs were identified in The Cancer Genome Atlas (TCGA) lung adenocarcinoma patient cohort (sequencing data; n=449) and subsequently validated by RT-qPCR in an independent clinical cohort (n=108)...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29326299/targeting-mutant-kras-with-crispr-cas9-controls-tumor-growth
#2
Hyongbum Henry Kim, Wonjoo Kim, Sangeun Lee, Han Sang Kim, Minjung Song, Yong Hoon Cha, Young-Hoon Kim, Jeonghong Shin, Eun-Seo Lee, Yeonsoo Joo, Jae J Song, Eun Ju Choi, Jae W Choi, Jinu Lee, Moonkyung Kang, Jong In Yook, Min Goo Lee, Yeon-Soo Kim, Soonmyung Paik
KRAS is the most frequently mutated oncogene in human tumors and its activating mutations represents important therapeutic targets. The combination of Cas9 and guide RNA from the CRISPR-Cas system recognizes a specific DNA sequence and makes a double-strand break, which enables editing of the relevant genes. Here we harnessed CRISPR to specifically target mutant KRAS alleles in cancer cells. We screened guide RNAs using a reporter system and validated them in cancer cells after lentiviral delivery of Cas9 and guide RNA...
January 11, 2018: Genome Research
https://www.readbyqxmd.com/read/29325430/rapid-and-sensitive-assessment-of-globin-chains-for-gene-and-cell-therapy-of-haemoglobinopathies
#3
Constantinos Christos Loucari, Petros Patsali, Thamar B van Dijk, Coralea Stephanou, Panayiota Papasavva, Maria Zanti, Ryo Kurita, Yukio Nakamura, Soteroulla Christou, Maria Sitarou, Sjaak Philipsen, Carsten Werner Lederer, Marina Kleanthous
The β-haemoglobinopathies sickle cell anaemia and β-thalassaemia are the focus of many gene-therapy studies. A key disease parameter is the abundance of globin chains, because it indicates the level of anaemia, likely toxicity of excess or aberrant globins, and therapeutic potential of induced or exogenous β-like globins. Reversed-phase high-performance liquid chromatography (HPLC) allows versatile and inexpensive globin quantification, but commonly applied protocols suffer either from long run times, high sample requirements or inability to separate murine from human β-globin chains...
January 12, 2018: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/29316283/split-cas9-not-hairs-advancing-the-therapeutic-index-of-crispr-technology
#4
REVIEW
Carolin Schmelas, Dirk Grimm
The discovery that the bacterial CRISPR/Cas9 system can be translated into mammalian cells continues to have an unprecedented impact on the biomedical research community, as it largely facilitates efforts to experimentally interrogate or therapeutically modify the cellular genome. In particular, CRISPR promises the ability to correct disease-associated genetic defects, or to target and destroy invading foreign DNA, in a simple, efficient and selective manner directly in affected human cells or tissues. Here, we highlight a set of exciting new strategies that aim at further increasing the therapeutic index of CRISPR technologies, by reducing the size of Cas9 expression cassettes and thus enhancing their compatibility with viral gene delivery vectors...
January 5, 2018: Biotechnology Journal
https://www.readbyqxmd.com/read/29314827/macrophage-specific-in-vivo-gene-editing-using-cationic-lipid-assisted-polymeric-nanoparticles
#5
Ying-Li Luo, Cong-Fei Xu, Hong-Jun Li, Zhi-Ting Cao, Jing Liu, Ji-Long Wang, Xiao-Jiao Du, Xian-Zhu Yang, Zhen Gu, Jun Wang
The CRISPR/Cas9 gene editing technology holds promise for the treatment of multiple diseases. However, the inability to perform specific gene editing in targeted tissues and cells, which may cause off-target effects, is one of the critical bottlenecks for therapeutic application of CRISPR/Cas9. Herein, macrophage-specific promoter-driven Cas9 expression plasmids (pM458 and pM330) were constructed and encapsulated in cationic lipid-assisted PEG-b-PLGA nanoparticles (CLAN). The obtained nanoparticles encapsulating the CRISPR/Cas9 plasmids were able to specifically express Cas9 in macrophages as well as their precursor monocytes both in vitro and in vivo...
January 9, 2018: ACS Nano
https://www.readbyqxmd.com/read/29311330/gba1-deficiency-negatively-affects-physiological-%C3%AE-synuclein-tetramers-and-related-multimers
#6
Sangjune Kim, Seung Pil Yun, Saebom Lee, George Essien Umanah, Veera Venkata Ratnam Bandaru, Xiling Yin, Peter Rhee, Senthilkumar S Karuppagounder, Seung-Hwan Kwon, Hojae Lee, Xiaobo Mao, Donghoon Kim, Akhilesh Pandey, Gabsang Lee, Valina L Dawson, Ted M Dawson, Han Seok Ko
Accumulating evidence suggests that α-synuclein (α-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of α-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of α-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of α-syn and leads to changes in neuronal glycosphingolipids (GSLs) including gangliosides, we hypothesized that GBA1 deficiency may affect the formation of α-syn tetramers...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29305085/engineering-the-delivery-system-for-crispr-based-genome-editing
#7
REVIEW
Zachary Glass, Matthew Lee, Yamin Li, Qiaobing Xu
Clustered regularly interspaced short palindromic repeat-CRISPR-associated protein (CRISPR-Cas) systems, found in nature as microbial adaptive immune systems, have been repurposed into an important tool in biological engineering and genome editing, providing a programmable platform for precision gene targeting. These tools have immense promise as therapeutics that could potentially correct disease-causing mutations. However, CRISPR-Cas gene editing components must be transported directly to the nucleus of targeted cells to exert a therapeutic effect...
January 2, 2018: Trends in Biotechnology
https://www.readbyqxmd.com/read/29304336/turning-up-the-heat-with-therapeutic-epigenome-editing
#8
Alexandra Zezulin, Kiran Musunuru
CRISPR-Cas9 has been touted for therapeutic genome editing, but limitations include inefficient correction of disease-causing mutations and off-target mutagenesis. In the latest issue of Cell, Liao et al. (2017) show that a modified version of CRISPR-Cas9 can target and activate key therapeutic genes in vivo without altering DNA sequence identity.
January 4, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29296828/gene-editing-rescue-of-a-novel-mpl-mutant-associated-with-congenital-amegakaryocytic-thrombocytopenia
#9
Cédric Cleyrat, Romain Girard, Eun H Choi, Éric Jeziorski, Thierry Lavabre-Bertrand, Sylvie Hermouet, Serge Carillo, Bridget S Wilson
Thrombopoietin (Tpo) and its receptor (Mpl) are the principal regulators of early and late thrombopoiesis and hematopoietic stem cell maintenance. Mutations in MPL can drastically impair its function and be a contributing factor in multiple hematologic malignancies, including congenital amegakaryocytic thrombocytopenia (CAMT). CAMT is characterized by severe thrombocytopenia at birth, which progresses to bone marrow failure and pancytopenia. Here we report unique familial cases of CAMT that presented with a previously unreported MPL mutation: T814C (W272R) in the background of the activating MPL G117T (K39N or Baltimore) mutation...
September 26, 2017: Blood Advances
https://www.readbyqxmd.com/read/29290616/reconstruction-of-the-human-colon-epithelium-in%C3%A2-vivo
#10
Shinya Sugimoto, Yuki Ohta, Masayuki Fujii, Mami Matano, Mariko Shimokawa, Kosaku Nanki, Shoichi Date, Shingo Nishikori, Yoshihiro Nakazato, Tetsuya Nakamura, Takanori Kanai, Toshiro Sato
Genetic lineage tracing has revealed that Lgr5+ murine colon stem cells (CoSCs) rapidly proliferate at the crypt bottom. However, the spatiotemporal dynamics of human CoSCs in vivo have remained experimentally intractable. Here we established an orthotopic xenograft system for normal human colon organoids, enabling stable reconstruction of the human colon epithelium in vivo. Xenografted organoids were prone to displacement by the remaining murine crypts, and this could be overcome by complete removal of the mouse epithelium...
December 21, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/29282220/inflammasome-adaptor-asc-suppresses-apoptosis-of-gastric-cancer-cells-by-an-il-18-mediated-inflammation-independent-mechanism
#11
Brendan J Jenkins, Virginie Deswaerte, Paul M Nguyen, Alison West, Alison F Browning, Liang Yu, Saleela Ruwanpura, Jesse Balic, Thaleia Livis, Charlotte Girard, Adele Preaudet, Hiroko Oshima, Ka Yee Fung, Hazel Tye, Meri Najdovska, Matthias Ernst, Masanobu Oshima, Cem Gabay, Tracy L Putoczki
Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a pro-tumorigenic role in gastric cancer (GC) for the key inflammasome adaptor ASC and its effector cytokine IL-18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type GC suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation...
December 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29281250/discovering-the-genome-wide-activity-of-crispr-cas-nucleases
#12
Shengdar Q Tsai
Originally discovered as part of an adaptive bacterial defense system against the invasion of foreign phages, programmable CRISPR-Cas nucleases have emerged as remarkable enzymes with transformative potential for both biological research and clinical application. CRISPR-Cas nucleases likely evolved in their natural context to tolerate imperfect specificity in order to recognize mutant bacteriophages. However, in the context of biological research and clinical applications, high specificity is generally preferred...
December 27, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29281027/cas9-sgrna-selective-targeting-of-the-p23h-rhodopsin-mutant-allele-for-treating-retinitis-pigmentosa-by-intravitreal-aav9-php-b-based-delivery
#13
Serena G Giannelli, Mirko Luoni, Valerio Castoldi, Luca Massimino, Tommaso Cabassi, Debora Angeloni, Giancarlo Demontis, Letizia Leocani, Massimiliano Andreazzoli, Vania Broccoli
P23H is the most common mutation in the RHODOPSIN (RHO) gene leading to a dominant form of Retinitis Pigmentosa (RP), a rod photoreceptor degeneration that invariably causes vision loss. Specific disruption of the disease P23H RHO mutant while preserving the wild-type functional allele would be an invaluable therapy for this disease. However, various technologies tested in the past failed to achieve effective changes and consequently therapeutic benefits. We validated a CRISPR/Cas9 strategy to specifically inactivate the P23H RHO mutant, while preserving the wild-type (WT) allele in vitro...
December 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29280958/development-of-novel-therapeutic-agents-by-inhibition-of-oncogenic-micrornas
#14
REVIEW
Dinh-Duc Nguyen, Suhwan Chang
MicroRNAs (miRs, miRNAs) are regulatory small noncoding RNAs, with their roles already confirmed to be important for post-transcriptional regulation of gene expression affecting cell physiology and disease development. Upregulation of a cancer-causing miRNA, known as oncogenic miRNA, has been found in many types of cancers and, therefore, represents a potential new class of targets for therapeutic inhibition. Several strategies have been developed in recent years to inhibit oncogenic miRNAs. Among them is a direct approach that targets mature oncogenic miRNA with an antisense sequence known as antimiR, which could be an oligonucleotide or miRNA sponge...
December 27, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29273498/engineering-protein-secreting-plasma-cells-by-homology-directed-repair-in-primary-human-b-cells
#15
King L Hung, Iana Meitlis, Malika Hale, Chun-Yu Chen, Swati Singh, Shaun W Jackson, Carol H Miao, Iram F Khan, David J Rawlings, Richard G James
The ability to engineer primary human B cells to differentiate into long-lived plasma cells and secrete a de novo protein may allow the creation of novel plasma cell therapies for protein deficiency diseases and other clinical applications. We initially developed methods for efficient genome editing of primary B cells isolated from peripheral blood. By delivering CRISPR/CRISPR-associated protein 9 (Cas9) ribonucleoprotein (RNP) complexes under conditions of rapid B cell expansion, we achieved site-specific gene disruption at multiple loci in primary human B cells (with editing rates of up to 94%)...
November 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29261286/crispr-approaches-to-small-molecule-target-identification
#16
Marco Jost, Jonathan S Weissman
A long-standing challenge in drug development is the identification of the mechanisms of action of small molecules with therapeutic potential. A number of methods have been developed to address this challenge, each with inherent strengths and limitations. We here provide a brief review of these methods with a focus on chemical-genetic methods that are based on systematically profiling the effects of genetic perturbations on drug sensitivity. In particular, application of these methods to mammalian systems has been facilitated by the recent advent of CRISPR-based approaches, which enable one to readily repress, induce, or delete a given gene...
December 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29260979/hspa5-negatively-regulates-lysosomal-activity-through-ubiquitination-of-mul1-in-head-and-neck-cancer
#17
Sun-Yong Kim, Hyo Jeong Kim, Haeng-Jun Kim, Dae Ho Kim, Chul-Ho Kim, Jae Ho Han, Hyung Kwon Byeon, Keunho Lee
HSPA5/GRP78/BiP plays an important role in cell survival or tumor progression. For these reasons, HSPA5 is an emerging therapeutic target in cancer development. Here we report that HSPA5 contributes to head and neck cancer (HNC) survival via maintenance of lysosomal activity; however, a nonthermal plasma (NTP, considered as a next-generation cancer therapy)-treated solution (NTS) inhibits HNC progression through HSPA5-dependent alteration of lysosomal activity. HSPA5 prevents NTS-induced lysosome inhibition through lysosomal-related proteins or regulation of gene expression...
December 20, 2017: Autophagy
https://www.readbyqxmd.com/read/29260740/-hepatitis-c-can-be-cured-will-hepatitis-b-become-next
#18
V P Chulanov, A P Zueva, D S Kostyushev, S A Brezgin, E V Volchkova, V V Maleyev
Chronic hepatitis B (CHB) and C (CHC) are one of the leading causes of cirrhosis and liver cancer with over a million of people dying annually from their consequences. In Russia CHB and CHC morbidity and related mortality show an upward trend. As a result of recent breakthroughs in antiviral therapeutics CHC became a curable disease. Modern therapeutics effectively suppress viral replication in CHB patients, but withdrawal of antivirals usually results in disease relapse. Loss of HBsAg required for the so called 'functional cure' is a very rare event...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/29259521/nuclease-mediated-gene-therapies-for-inherited-metabolic-diseases-of-the-liver%C3%A2-%C3%A2
#19
REVIEW
Taylor E Bryson, Caitlin M Anglin, P Hudson Bridges, Renee N Cottle
Inherited metabolic diseases (IMDs) of the liver represent a vast and diverse group of rare genetic diseases characterized by the loss or dysfunction of enzymes or proteins essential for metabolic pathways in the liver. Conventional gene therapy involving adeno-associated virus (AAV) serotype 8 vectors provide therapeutically high levels of hepatic transgene expression facilitating the correction of the disease phenotype in pre-clinical studies and are currently being evaluated in clinical trials for multiple IMDs...
December 2017: Yale Journal of Biology and Medicine
https://www.readbyqxmd.com/read/29259519/%C3%A2-the-application-of-crispr-cas9-for-the-treatment-of-retinal-diseases%C3%A2
#20
REVIEW
Caroline F Peddle, Robert E MacLaren
The CRISPR/Cas9 system of genome editing has revolutionized molecular biology, offering a simple, and relatively inexpensive method of creating precise DNA edits. It has potential application in gene therapy treatment of retinal diseases providing targeted disruption, alteration, or transcriptional regulation of pathogenic genes. In vivo studies have demonstrated therapeutic benefit for a variety of diseases. Despite this, there are many challenges to clinical use of CRISPR/Cas9, including editing efficiency, off-target effects, and disease heterogeneity...
December 2017: Yale Journal of Biology and Medicine
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