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Anti crispr

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https://www.readbyqxmd.com/read/27896818/coupling-immunity-and-programmed-cell-suicide-in-prokaryotes-life-or-death-choices
#1
Eugene V Koonin, Feng Zhang
Host-pathogen arms race is a universal, central aspect of the evolution of life. Most organisms evolved several distinct yet interacting strategies of anti-pathogen defense including resistance to parasite invasion, innate and adaptive immunity, and programmed cell death (PCD). The PCD is the means of last resort, a suicidal response to infection that is activated when resistance and immunity fail. An infected cell faces a decision between active defense and altruistic suicide or dormancy induction, depending on whether immunity is "deemed" capable of preventing parasite reproduction and consequent infection of other cells...
November 29, 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/27862436/redefining-the-phenotype-of-heat-shock-protein-90-hsp90-inhibitors
#2
Yao Wang, Yen Chin Koay, Shelli Renee McAlpine
Comparing the phenotypes produced when cells are treated with the Hsp90 inhibitors AUY922 or 17-AAG (classical inhibitors) to cells with Hsp90alpha knocked down reveals that the knockdown phenotype is unique from that produced by the inhibitors. Pull-down assays using classical inhibitors verify that these molecules do not bind to Hsp90 as their primary target. Classical inhibitors induce similar protein markers as other anti-cancer therapies Cisplatin and bortezomib, suggesting that AUY922 and 17-AAG act on targets other than Hsp90 and kill cells through multiple mechanisms...
November 8, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27837168/microbial-derived-1-4-dihydroxy-2-naphthoic-acid-and-related-compounds-as-aryl-hydrocarbon-receptor-agonists-antagonists-structure-activity-relationships-and-receptor-modeling
#3
Yating Cheng, Un-Ho Jin, Laurie A Davidson, Robert S Chapkin, Arul Jayaraman, Phanourios Tamamis, Asuka Orr, Clint Allred, Michael S Denison, Anatoly Soshilov, Evelyn Weaver, Stephen Safe
1,4-Dihydroxy-2-naphthoic acid (1,4-DHNA) is a bacterial-derived metabolite that binds the aryl hydrocarbon receptor (AhR) and exhibits anti-inflammatory activity in the gut. The structure-dependent AhR activity of hydroxyl/carboxy-substituted naphthoic acids was determined in young adult mouse colonic (YAMC) cells and human Caco2 colon cancer cells using CYP1A1/CYP1B1 mRNAs as Ah-responsive genes. Compounds used in this study include 1,4-, 3,5- and 3,7-DHNA, 1,4-dimethoxy-2-naphthoic acid (1,4-DMNA), 1- and 4-hydroxy-2-naphthoic acid (1-HNA, 4-HNA), 1- and 2-naphthoic acid (1-NA, 2-NA), and 1- and 2-naphthol (1-NOH, 2-NOH)...
November 11, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/27815355/multiplex-genome-editing-to-generate-universal-car-t-cells-resistant-to-pd1-inhibition
#4
Jiangtao Ren, Xiaojun Liu, Chongyun Fang, Shuguang Jiang, Carl H June, Yangbing Zhao
PURPOSE: Using gene-disrupted allogeneic T cells as universal effector cells provides an alternative to and potentially improves current chimeric antigen receptor (CAR) T cell therapy against cancers and infectious diseases. EXPERIMENTAL DESIGN: The CRISPR/Cas9 system has recently emerged as a simple and efficient way for multiplex genome engineering. By combining the lentiviral delivery of CAR and CRISPR RNA electroporation to co-introduce RNA encoding the Cas9 and gRNAs targeting endogenous TCR, beta-2 microglobulin (B2M) and PD1 simultaneously, to generate gene-disrupted allogeneic CAR T cells deficient of TCR, HLA class I molecule and PD1...
November 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27815036/crispr-mediated-targeting-of-her2-inhibits-cell-proliferation-through-a-dominant-negative-mutation
#5
Huajing Wang, William Sun
With the discovery of the CRISPR/Cas9 technology, genome editing could be performed in a rapid, precise and effective manner. Its potential applications in functional interrogation of cancer-causing genes and cancer therapy have been extensively explored. In this study, we demonstrated the use of the CRISPR/Cas9 system to directly target the oncogene HER2. Directing Cas9 to exons of the HER2 gene inhibited cell growth in breast cancer cell lines that harbor amplification of the HER2 locus. The inhibitory effect was potentiated with the addition of PARP inhibitors...
November 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27806571/knockout-of-the-ribonuclease-inhibitor-gene-leaves-human-cells-vulnerable-to-secretory-ribonucleases
#6
Sydney P Thomas, Eunji Kim, Jin-Soo Kim, Ronald T Raines
Ribonuclease inhibitor (RNH1) is a cytosolic protein that binds with femtomolar affinity to human ribonuclease 1 (RNase 1) and homologous secretory ribonucleases. RNH1 contains 32 cysteine residues and has been implicated as an anti-oxidant. Here, we use CRISPR-Cas9 to knockout RNH1 in HeLa cells. We find that cellular RNH1 affords marked protection from the lethal ribonucleolytic activity of RNase 1 but not from oxidants. We conclude that RNH1 protects cytosolic RNA from invading ribonucleases.
November 2, 2016: Biochemistry
https://www.readbyqxmd.com/read/27799325/muts2-promotes-homologous-recombination-in-bacillus-subtilis
#7
Peter E Burby, Lyle A Simmons
: Bacterial MutS proteins are subdivided into two families, MutS1 and MutS2. MutS1 family members recognize DNA replication errors during their participation in the well-characterized mismatch repair pathway (MMR). In contrast, to the well-described function of MutS1, the function of MutS2 in bacteria has remained less clear. In Helicobacter pylori and Thermus thermophilus, MutS2 has been shown to suppress homologous recombination. The role of MutS2 is unknown in the Gram-positive bacterium Bacillus subtilis In this work, we investigated the contribution of MutS2 to maintaining genome integrity in B...
October 31, 2016: Journal of Bacteriology
https://www.readbyqxmd.com/read/27786251/ovariectomy-upregulated-the-expression-of-peroxiredoxin-1-5-in-osteoblasts-of-mice
#8
Juan Du, Wei Feng, Jing Sun, Cuijie Kang, Norio Amizuka, Minqi Li
Peroxiredoxin (PRX), a family of peroxidases, is associated with various biological processes such as the detoxification of oxidants and cell apoptosis. Besides, the anti-apoptosis effect of estrogen results partially from its anti-oxidant function. The purpose of this study was to investigate the expression of PRXs in ovariectomy (OVX) mice and the related anti-oxidative mechanism of estrogen. Eight-week-old mice were subjected to ovariectomy. MC3T3-E1 cells were pretreatment with 17b-estradiol and N-acetyl cysteine followed by oxidative injury induced with H2O2...
October 27, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27784791/an-affinity-directed-protein-missile-system-for-targeted-proteolysis
#9
Luke J Fulcher, Thomas Macartney, Polyxeni Bozatzi, Annika Hornberger, Alejandro Rojas-Fernandez, Gopal P Sapkota
The von Hippel-Lindau (VHL) protein serves to recruit the hypoxia-inducible factor alpha (HIF1α) protein under normoxia to the CUL2 E3 ubiquitin ligase for its ubiquitylation and degradation through the proteasome. In this report, we modify VHL to engineer an affinity-directed protein missile (AdPROM) system to direct specific endogenous target proteins for proteolysis in mammalian cells. The proteolytic AdPROM construct harbours a cameloid anti-green fluorescence protein (aGFP) nanobody that is fused to VHL for either constitutive or tetracycline-inducible expression...
October 2016: Open Biology
https://www.readbyqxmd.com/read/27780859/the-second-generation-exportin-1-inhibitor-kpt-8602-demonstrates-potent-activity-against-acute-lymphoblastic-leukemia
#10
Thomas Vercruysse, Jolien De Bie, Jasper Neggers, Maarten Jacquemyn, Els Vanstreels, Jonathan Leo Schmid-Burgk, Veit Hornung, Erkan Baloglu, Yosef Landesman, William Senapedis, Sharon Shacham, Antonis Dagklis, Jan Cools, Dirk Daelemans
PURPOSE: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports many cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibition of XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in Phase-II/IIb clinical trials when dosed 1 - 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27760321/a-crispr-dropout-screen-identifies-genetic-vulnerabilities-and-therapeutic-targets-in-acute-myeloid-leukemia
#11
Konstantinos Tzelepis, Hiroko Koike-Yusa, Etienne De Braekeleer, Yilong Li, Emmanouil Metzakopian, Oliver M Dovey, Annalisa Mupo, Vera Grinkevich, Meng Li, Milena Mazan, Malgorzata Gozdecka, Shuhei Ohnishi, Jonathan Cooper, Miten Patel, Thomas McKerrell, Bin Chen, Ana Filipa Domingues, Paolo Gallipoli, Sarah Teichmann, Hannes Ponstingl, Ultan McDermott, Julio Saez-Rodriguez, Brian J P Huntly, Francesco Iorio, Cristina Pina, George S Vassiliou, Kosuke Yusa
Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates...
October 18, 2016: Cell Reports
https://www.readbyqxmd.com/read/27758144/genetically-engineered-macrophages-a-potential-platform-for-cancer-immunotherapy
#12
Kara W Moyes, Nicole A P Lieberman, Shannon A Kreuser, Harrison Chinn, Conrad Winter, Gail Deutsch, Virginia Hoglund, Reid Watson, Courtney A Crane
In spite of their successes against hematologic malignancies, immunotherapeutic interventions for the treatment of patients with glioblastoma (GBM) have thus far been unsuccessful. This is in part due to the presence of a tumor microenvironment that fosters neoplastic growth and protects the tumor from destruction by the immune system. A novel genetically engineered macrophage-based platform has been developed with the potential to minimize the effects of the suppressive tumor microenvironment and improve innate and adaptive antitumor immune responses...
October 18, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27748765/genomic-modelling-of-the-esr1-y537s-mutation-for-evaluating-function-and-new-therapeutic-approaches-for-metastatic-breast-cancer
#13
A Harrod, J Fulton, V T M Nguyen, M Periyasamy, L Ramos-Garcia, C-F Lai, G Metodieva, A de Giorgio, R L Williams, D B Santos, P J Gomez, M-L Lin, M V Metodiev, J Stebbing, L Castellano, L Magnani, R C Coombes, L Buluwela, S Ali
Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations...
October 17, 2016: Oncogene
https://www.readbyqxmd.com/read/27725669/the-solution-structure-of-an-anti-crispr-protein
#14
Karen L Maxwell, Bianca Garcia, Joseph Bondy-Denomy, Diane Bona, Yurima Hidalgo-Reyes, Alan R Davidson
Bacterial CRISPR-Cas adaptive immune systems use small guide RNAs to protect against phage infection and invasion by foreign genetic elements. We previously demonstrated that a group of Pseudomonas aeruginosa phages encode anti-CRISPR proteins that inactivate the type I-F and I-E CRISPR-Cas systems using distinct mechanisms. Here, we present the three-dimensional structure of an anti-CRISPR protein and map a functional surface that is critical for its potent inhibitory activity. The interaction of the anti-CRISPR protein with the CRISPR-Cas complex through this functional surface is proposed to prevent the binding of target DNA...
October 11, 2016: Nature Communications
https://www.readbyqxmd.com/read/27713537/increasing-the-efficiency-of-crispr-cas9-mediated-precise-genome-editing-of-hsv-1-virus-in-human-cells
#15
Chaolong Lin, Huanhuan Li, Mengru Hao, Dan Xiong, Yong Luo, Chenghao Huang, Quan Yuan, Jun Zhang, Ningshao Xia
Genetically modified HSV-1 viruses serve as promising vectors for tumour therapy and vaccine development. The CRISPR/Cas9 system is one of the most powerful tools for precise gene editing of the genomes of organisms. However, whether the CRISPR/Cas9 system can precisely and efficiently make gene replacements in the genome of HSV-1 remains essentially unknown. Here, we reported CRISPR/Cas9-mediated editing of the HSV-1 genome in human cells, including the knockout and replacement of large genes. In established cells stably expressing CRISPR/Cas9, gRNA in coordination with Cas9 could direct a precise cleavage within a pre-defined target region, and foreign genes were successfully used to replace the target gene seamlessly by HDR-mediated gene replacement...
October 7, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27681120/altering-the-anti-inflammatory-lipoxin-microenvironment-a-new-insight-into-kaposi-s-sarcoma-associated-herpesvirus-pathogenesis
#16
Jayashree A Chandrasekharan, Xiao M Huang, Alexander C Hwang, Neelam Sharma-Walia
: Lipoxins are host anti-inflammatory molecules that play a vital role in restoring tissue homeostasis. The efficacy of lipoxins and their analog epilipoxins in treating inflammation and its associated diseases has been well documented. Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL) are two well-known inflammation related diseases caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Controlling inflammation is one of the strategies adopted to treat KS and PEL, a primary motivation for exploring and evaluating the therapeutic potential of using lipoxins...
December 15, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27678060/characterization-of-aspartyl-aminopeptidase-from-toxoplasma-gondii
#17
Jun Zheng, Ziying Cheng, Honglin Jia, Yonghui Zheng
Aminopeptidases have emerged as new promising drug targets for the development of novel anti-parasitic drugs. An aspartyl aminopeptidase-like gene has been identified in the Toxoplasma gondii genome (TgAAP), although its function remains unknown. In this study, we characterized TgAAP and performed functional analysis of the gene product. Firstly, we expressed a functional recombinant TgAAP (rTgAAP) protein in Escherichia coli, and found that it required metal ions for activity and showed a substrate preference for N-terminal acidic amino acids Glu and Asp...
September 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27664857/determining-antigen-specificity-of-a-monoclonal-antibody-using-genome-scale-crispr-cas9-knockout-library
#18
Anastasia Zotova, Ivan Zotov, Alexander Filatov, Dmitriy Mazurov
An essential step in monoclonal antibody (mAb) development is the characterization and final identification of the specific target antigen and its epitope. Antibody validation is rather straightforward when immunization is carried out with peptide or purified protein, but is more difficult when whole cells or other complex antigens are used for the immunization. Determining antigen specificity of a mAb is further complicated, when reactivity of an antibody is not detected in Western blotting and/or immunoprecipitation assay...
September 21, 2016: Journal of Immunological Methods
https://www.readbyqxmd.com/read/27661404/pcm1-depletion-inhibits-glioblastoma-cell-ciliogenesis-and-increases-cell-death-and-sensitivity-to-temozolomide
#19
Lan B Hoang-Minh, Loic P Deleyrolle, Nariaki S Nakamura, Alexander K Parker, Regina T Martuscello, Brent A Reynolds, Matthew R Sarkisian
A better understanding of the molecules implicated in the growth and survival of glioblastoma (GBM) cells and their response to temozolomide (TMZ), the standard-of-care chemotherapeutic agent, is necessary for the development of new therapies that would improve the outcome of current GBM treatments. In this study, we characterize the role of pericentriolar material 1 (PCM1), a component of centriolar satellites surrounding centrosomes, in GBM cell proliferation and sensitivity to genotoxic agents such as TMZ...
October 2016: Translational Oncology
https://www.readbyqxmd.com/read/27641735/microrna-1304-suppresses-human-non-small-cell-lung-cancer-cell-growth-in-vitro-by-targeting-heme-oxygenase-1
#20
Cheng-Gang Li, Meng-Fan Pu, Chun-Zhu Li, Man Gao, Ming-Xia Liu, Cun-Zhi Yu, Hong Yan, Chun Peng, Yang Zhao, Yu Li, Ze-Long Ma, Xin-Ming Qi, Yi-Zheng Wang, Ling-Ling Miao, Jin Ren
AIM: Previous studies have shown that microRNA-1304 (miR-1304) is dysregulated in certain types of cancers, including non-small cell lung cancer (NSCLC), and might be involved in tumor survival and/or growth. In this study we investigated the direct target of miR-1304 and its function in NSCLC in vitro. METHODS: Human lung adenocarcinoma cell lines (A549 and NCI-H1975) were studied. The cell proliferation and survival were investigated via cell counting, MTT and colony-formation assays...
September 19, 2016: Acta Pharmacologica Sinica
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