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https://www.readbyqxmd.com/read/28434148/advancing-chimeric-antigen-receptor-t-cell-therapy-with-crispr-cas9
#1
REVIEW
Jiangtao Ren, Yangbing Zhao
The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (CRISPR/Cas9) system, an RNA-guided DNA targeting technology, is triggering a revolution in the field of biology. CRISPR/Cas9 has demonstrated great potential for genetic manipulation. In this review, we discuss the current development of CRISPR/Cas9 technologies for therapeutic applications, especially chimeric antigen receptor (CAR) T cell-based adoptive immunotherapy. Different methods used to facilitate efficient CRISPR delivery and gene editing in T cells are compared...
April 22, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28434147/increasing-the-safety-and-efficacy-of-chimeric-antigen-receptor-t-cell-therapy
#2
REVIEW
Hua Li, Yangbing Zhao
Chimeric antigen receptor (CAR) T cell therapy is a promising cancer treatment that has recently been undergoing rapid development. However, there are still some major challenges, including precise tumor targeting to avoid off-target or "on-target/off-tumor" toxicity, adequate T cell infiltration and migration to solid tumors and T cell proliferation and persistence across the physical and biochemical barriers of solid tumors. In this review, we focus on the primary challenges and strategies to design safe and effective CAR T cells, including using novel cutting-edge technologies for CAR and vector designs to increase both the safety and efficacy, further T cell modification to overcome the tumor-associated immune suppression, and using gene editing technologies to generate universal CAR T cells...
April 22, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28433539/rationally-designed-pi3k%C3%AE-mutants-to-mimic-atr-and-their-use-to-understand-binding-specificity-of-atr-inhibitors
#3
Yipin Lu, Mark Knapp, Kenneth Crawford, Robert Warne, Robert Elling, Kelly Yan, Michael Doyle, Gwynn Pardee, Li Zhang, Sylvia Ma, Mulugeta Mamo, Elizabeth Ornelas, Yue Pan, Dirksen Bussiere, Johanna Jansen, Isabel Zaror, Albert Lai, Paul Barsanti, Janet Sim
ATR, a protein kinase in the PIKK family, plays a critical role in the cell DNA-damage response and is an attractive anticancer drug target. Several potent and selective inhibitors of ATR have been reported showing significant antitumor efficacy, with most advanced ones entering clinical trials. However, due to the absence of an experimental ATR structure, the determinants contributing to ATR inhibitors' potency and specificity are not well understood. Here we present the mutations in the ATP-binding site of PI3Kα to progressively transform the pocket to mimic that of ATR...
April 19, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28433515/understanding-clinical-development-of-chimeric-antigen-receptor-t-cell-therapies
#4
Sofieke de Wilde, Henk-Jan Guchelaar, Maarten Laurens Zandvliet, Pauline Meij
BACKGROUND AIMS: In the past decade, many clinical trials with gene- and cell-based therapies (GCTs) have been performed. Increased interest in the development of these drug products by various stakeholders has become apparent. Despite this growth in clinical studies, the number of therapies receiving marketing authorization approval (MAA) is lagging behind. To enhance the success rate of GCT development, it is essential to better understand the clinical development of these products...
April 19, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28433078/haplotype-counting-for-sensitive-chimerism-testing-potential-for-early-leukemia-relapse-detection
#5
Marija Debeljak, Evelina Mocci, Max C Morrison, Aparna Pallavajjalla, Katie Beierl, Marie Amiel, Michaël Noë, Laura D Wood, Ming-Tseh Lin, Christopher D Gocke, Alison P Klein, Ephraim J Fuchs, Richard J Jones, James R Eshleman
Fields of forensics, transplantation, and paternity rely on human identity testing. Currently, this is accomplished through amplification of microsatellites followed by capillary electrophoresis. An alternative and theoretically better approach uses multiple single-nucleotide polymorphisms located within a small region of DNA, a method we initially developed using HLA-A and called haplotype counting. Herein, we validated seven additional polymorphic loci, sequenced a total of 45 individuals from three of the 1000 Genomes populations (15 from each), and determined the number of haplotypes, heterozygosity, and polymorphic information content for each locus...
May 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28432355/basal-autophagy-prevents-autoactivation-or-enhancement-of-inflammatory-signals-by-targeting-monomeric-myd88
#6
Takeshi Into, Toshi Horie, Megumi Inomata, Jin Gohda, Jun-Ichiro Inoue, Yukitaka Murakami, Shumpei Niida
Autophagy, the processes of delivery of intracellular components to lysosomes, regulates induction of inflammation. Inducible macroautophagy degrades inflammasomes and dysfunctional mitochondria to downregulate inflammatory signals. Nonetheless, the effects of constitutive basal autophagy on inflammatory signals are largely unknown. Here, we report a previously unknown effect of basal autophagy. Lysosomal inhibition induced weak inflammatory signals in the absence of a cellular stimulus and in the presence of a nutrient supply, and their induction was impaired by MyD88 deficiency...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28432147/cutting-edge-a-dual-tlr2-and-tlr7-ligand-induces-highly-potent-humoral-and-cell-mediated-immune-responses
#7
Alice Gutjahr, Laura Papagno, Francesco Nicoli, Alain Lamoureux, Fabienne Vernejoul, Thierry Lioux, Emma Gostick, David A Price, Gérard Tiraby, Eric Perouzel, Victor Appay, Bernard Verrier, Stéphane Paul
TLR agonists are currently being developed and tested as adjuvants in various formulations to optimize the immunogenicity and efficacy of vaccines. The aim of this study was to evaluate the immunostimulatory properties of a novel compound incorporating covalently linked moieties designed to stimulate both TLR2 and TLR7. This dual TLR2/TLR7 agonist induced the maturation of dendritic cells and primed substantial populations of cytolytic and highly polyfunctional effector CD8(+) T cells in vitro, and safely potentiated the immunogenic properties of a nanoparticulate Ag in vivo, eliciting humoral responses with a balanced TH1/TH2 profile in mice...
April 21, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28431573/a-highly-pathogenic-simian-human-immunodeficiency-virus-effectively-produces-infectious-virions-compared-with-a-less-pathogenic-virus-in-cell-culture
#8
Shoya Iwanami, Yusuke Kakizoe, Satoru Morita, Tomoyuki Miura, Shinji Nakaoka, Shingo Iwami
BACKGROUND: The host range of human immunodeficiency virus (HIV) is quite narrow. Therefore, analyzing HIV-1 pathogenesis in vivo has been limited owing to lack of appropriate animal model systems. To overcome this, chimeric simian and human immunodeficiency viruses (SHIVs) that encode HIV-1 Env and are infectious to macaques have been developed and used to investigate the pathogenicity of HIV-1 in vivo. So far, we have many SHIV strains that show different pathogenesis in macaque experiments...
April 21, 2017: Theoretical Biology & Medical Modelling
https://www.readbyqxmd.com/read/28429771/crispr-cas9-mediated-genome-editing-in-one-blastomere-of-two-cell-embryos-reveals-a-novel-tet3-function-in-regulating-neocortical-development
#9
Lingbo Wang, Min-Yin Li, Chao Qu, Wan-Ying Miao, Qi Yin, Jiaoyang Liao, Hua-Teng Cao, Min Huang, Kai Wang, Erwei Zuo, Guangdun Peng, Shu-Xin Zhang, Guodong Chen, Qing Li, Ke Tang, Qian Yu, Zhoujie Li, Catherine Cl Wong, Guoliang Xu, Naihe Jing, Xiang Yu, Jinsong Li
Studying the early function of essential genes is an important and challenging problem in developmental biology. Here, we established a method for rapidly inducing CRISPR-Cas9-mediated mutations in one blastomere of two-cell stage embryos, termed 2-cell embryo-CRISPR-Cas9 injection (2CC), to study the in vivo function of essential (or unknown) genes in founder chimeric mice. By injecting both Cre mRNA and CRISPR-Cas9 targeting the gene of interest into fluorescent reporter mice, the 2CC method can trace both wild-type and mutant cells at different developmental stages, offering internal control for phenotypic analyses of mutant cells...
April 21, 2017: Cell Research
https://www.readbyqxmd.com/read/28428885/the-why-what-and-how-of-the-new-fact-standards-for-immune-effector-cells
#10
EDITORIAL
Marcela V Maus, Sarah Nikiforow
Novel cellular therapies outside of traditional hematopoietic stem cell transplantation or hematopoietic progenitor cell (HPC) therapy are currently under evaluation in clinical trials across the United States and around the world. Several cellular products, e.g., CD19-directed Chimeric Antigen Receptor (CAR) T cells, are poised for FDA approval and thus increased use at a wider range of academic centers within the next year, with the likelihood of dissemination to standard oncology practice once safety is confirmed...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28428809/leucine-rich-repeat-containing-variable-lymphocyte-receptors-as-modules-to-target-plant-expressed-proteins
#11
André C Velásquez, Kinya Nomura, Max D Cooper, Brantley R Herrin, Sheng Yang He
BACKGROUND: The ability to target and manipulate protein-based cellular processes would accelerate plant research; yet, the technology to specifically and selectively target plant-expressed proteins is still in its infancy. Leucine-rich repeats (LRRs) are ubiquitously present protein domains involved in mediating protein-protein interactions. LRRs confer the binding specificity to the highly diverse variable lymphocyte receptor (VLR) antibodies (including VLRA, VLRB and VLRC types) that jawless vertebrates make as the functional equivalents of jawed vertebrate immunoglobulin-based antibodies...
2017: Plant Methods
https://www.readbyqxmd.com/read/28428075/immunotherapy-of-hepatocellular-carcinoma-using-chimeric-antigen-receptors-and-bispecific-antibodies
#12
Sayed Shahabuddin Hoseini, Nai-Kong V Cheung
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling...
April 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28427767/%C3%AE-arrestins-negatively-control-human-adrenomedullin-type-1-receptor-internalization
#13
Kenji Kuwasako, Kazuo Kitamura, Sayaka Nagata, Toshio Sekiguchi, Jiang Danfeng, Manabu Murakami, Yuichi Hattori, Johji Kato
Adrenomedullin (AM) is a potent hypotensive peptide that exerts a powerful variety of protective effects against multiorgan damage through the AM type 1 receptor (AM1 receptor), which consists of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (RAMP2). Two β-arrestin (β-arr) isoforms, β-arr-1 and β-arr-2, play a central role in the agonist-induced internalization of many receptors for receptor resensitization. Notably, β-arr-biased agonists are now being tested in phase II clinical trials, targeting acute pain and acute heart failure...
April 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28427300/object-decision-test-borb-normative-data-for-the-adult-quebec-population-and-performance-in-alzheimer-s-disease-and-the-semantic-variant-of-primary-progressive-aphasia
#14
Alexandre St-Hilaire, Marie-Claude Blackburn, Maximiliano A Wilson, Robert Jr Laforce, Carol Hudon, Joël Macoir
Object decision (OD) test is one subtest of the Birmingham Object Recognition Battery (BORB). It is useful for differential diagnosis among several neurodegenerative diseases. However, normative data provided with this battery count on very few subjects and do not control for the effect of age, which limits interpretability. The purpose of Study 1 was to provide normative data for the OD test of the BORB (version A-hard). The objectives of Study 2 were to establish the diagnostic validity of this task and predictive validity of the normative data in the case of the semantic variant of primary progressive aphasia (svPPA) and Alzheimer's disease (AD)...
April 21, 2017: Neuropsychology, Development, and Cognition. Section B, Aging, Neuropsychology and Cognition
https://www.readbyqxmd.com/read/28426845/her2-specific-chimeric-antigen-receptor-modified-virus-specific-t-cells-for-progressive-glioblastoma-a-phase-1-dose-escalation-trial
#15
Nabil Ahmed, Vita Brawley, Meenakshi Hegde, Kevin Bielamowicz, Mamta Kalra, Daniel Landi, Catherine Robertson, Tara L Gray, Oumar Diouf, Amanda Wakefield, Alexia Ghazi, Claudia Gerken, Zhongzhen Yi, Aidin Ashoori, Meng-Fen Wu, Hao Liu, Cliona Rooney, Gianpietro Dotti, Adrian Gee, Jack Su, Yvonne Kew, David Baskin, Yi Jonathan Zhang, Pamela New, Bambi Grilley, Milica Stojakovic, John Hicks, Suzanne Z Powell, Malcolm K Brenner, Helen E Heslop, Robert Grossman, Winfried S Wels, Stephen Gottschalk
Importance: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. Objective: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. Design, Setting, and Participants: In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014...
April 20, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28424711/genomic-molecular-evolution-and-expression-analysis-of-genes-encoding-putative-classical-agps-lysine-rich-agps-and-ag-peptides-in-brassica-rapa
#16
Tianyu Han, Heng Dong, Jie Cui, Ming Li, Sue Lin, Jiashu Cao, Li Huang
Arabinogalactan proteins (AGPs) belong to a class of Pro/Hyp-rich glycoproteins and are some of the most complex types of macromolecules found in plants. In the economically important plant species, Brassica rapa, only chimeric AGPs have been identified to date. This has significantly limited our understanding of the functional roles of AGPs in this plant. In this study, 64 AGPs were identified in the genome of B. rapa, including 33 classical AGPs, 28 AG peptides and three lys-rich AGPs. Syntenic gene analysis between B...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28423714/usefulness-of-the-mrp2-promoter-to-overcome-the-chemoresistance-of-gastrointestinal-and-liver-tumors-by-enhancing-the-expression-of-the-drug-transporter-oatp1b1
#17
Elisa Herraez, Laura Sanchez-Vicente, Rocio I R Macias, Oscar Briz, Jose J G Marin
Tumor response to chemotherapy is often limited by drug export through ABC proteins. To overcome this problem, here we have investigated the usefulness of inducing the expression of the multidrug uptake transporter OATP1B1 under the control of the MRP2 promoter (MRP2pr). Human hepatoma cells (Alexander) were transfected with MRP2pr fragments of different length fused to the firefly luciferase ORF in order to select the shortest fragment with the highest response to dexamethasone, which was subsequently used to generate the chimeric construct MRP2pr-OATP1B1-V5...
March 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423057/insertion-of-a-ligand-to-her2-in-gb-retargets-hsv-tropism-and-obviates-the-need-for-activation-of-the-other-entry-glycoproteins
#18
Biljana Petrovic, Tatiana Gianni, Valentina Gatta, Gabriella Campadelli-Fiume
Herpes simplex virus (HSV) entry into the cells requires glycoproteins gD, gH/gL and gB, activated in a cascade fashion by conformational modifications induced by cognate receptors and intermolecular signaling. The receptors are nectin1 and HVEM (Herpes virus entry mediator) for gD, and αvβ6 or αvβ8 integrin for gH. In earlier work, insertion of a single chain antibody (scFv) to the cancer receptor HER2 (human epidermal growth factor receptor 2) in gD, or in gH, resulted in HSVs specifically retargeted to the HER2-positive cancer cells, hence in highly specific non-attenuated oncolytic agents...
April 19, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28422403/blood-chimerism-in-dizygotic-monochorionic-twins-during-five-years-observation
#19
Morten Hanefeld Dziegiel, Morten Høgh Hansen, Sofie Haedersdal, Angela Natalie Barrett, Klaus Rieneck, Katharina Maria Main, Anne Todsen Hansen, Frederik Banch Clausen
Dizygotic monochorionic twin pregnancies can result in blood chimerism due to in utero twin-to-twin exchange of stem cells. In this case, we examined the proportion of allogeneic red blood cells (RBCs) by flow cytometry and the proportion of allogeneic nucleated cells by digital PCR at seven months and again at five years. We found an increase in the proportion of allogeneic cells from 63% to 89% in one twin, and a similar increase in autologous cells in the other twin from 57% to 84%. A paradigm for stem cell therapy could be modelled on this case: induction of tolerance and chimerism by antenatal transfusion of donor stem cells...
April 19, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28422137/effective-in-vivo-therapeutic-igg-antibody-against-vp3-of-enterovirus-71-with-receptor-competing-activity
#20
Qiang Jia, Qingyong Ng, Wenjie Chin, Tao Meng, Vincent Tak Kwong Chow, Cheng-I Wang, Jimmy Kwang, Fang He
Passive immunization is an effective option for treatment against hand, foot and mouth disease caused by EV71, especially with cross-neutralizing IgG monoclonal antibodies. In this study, an EV71-specific IgG2a antibody designated 5H7 was identified and characterized. 5H7 efficiently neutralizes the major EV71 genogroups (A, B4, C2, C4). The conformational epitope of 5H7 was mapped to the highly conserved amino acid position 74 on VP3 capsid protein using escape mutants. Neutralization with 5H7 is mediated by the inhibition of viral attachment, as revealed by virus-binding and post-attachment assays...
April 19, 2017: Scientific Reports
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