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https://www.readbyqxmd.com/read/28104689/identification-of-apilimod-as-a-first-in-class-pikfyve-kinase-inhibitor-for-treatment-of-b-cell-non-hodgkin-lymphoma
#1
Sophia Gayle, Sean Landrette, Neil Beeharry, Chris Conrad, Marylens Hernandez, Paul Beckett, Shawn M Ferguson, Talya Mandelkern, Meiling Zheng, Tian Xu, Jonathan Rothberg, Henri Lichenstein
We identified apilimod as an anti-proliferative compound by high-throughput screening of clinical stage drugs. Apilimod exhibits exquisite specificity for PIKfyve lipid kinase and has selective cytotoxic activity in B-cell non-Hodgkin lymphoma (B-NHL) compared to normal cells. Apilimod displays nanomolar activity in vitro, and in vivo studies demonstrate single agent efficacy as well as synergy with approved B-NHL drugs. Using biochemical and knockdown approaches, and discovery of a kinase domain mutation conferring resistance, we demonstrate that apilimod-mediated cytotoxicity is driven by PIKfyve inhibition...
January 19, 2017: Blood
https://www.readbyqxmd.com/read/28101903/development-and-characterization-of-anti-glycopeptide-monoclonal-antibodies-against-human-podoplanin-using-glycan-deficient-cell-lines-generated-by-crispr-cas9-and-talen
#2
Mika K Kaneko, Takuro Nakamura, Ryusuke Honma, Satoshi Ogasawara, Yuki Fujii, Shinji Abe, Michiaki Takagi, Hiroyuki Harada, Hiroyoshi Suzuki, Yasuhiko Nishioka, Yukinari Kato
Human podoplanin (hPDPN), which binds to C-type lectin-like receptor-2 (CLEC-2), is involved in platelet aggregation and cancer metastasis. The expression of hPDPN in cancer cells or cancer-associated fibroblasts indicates poor prognosis. Human lymphatic endothelial cells, lung-type I alveolar cells, and renal glomerular epithelial cells express hPDPN. Although numerous monoclonal antibodies (mAbs) against hPDPN are available, they recognize peptide epitopes of hPDPN. Here, we generated a novel anti-hPDPN mAb, LpMab-21...
January 19, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28067257/enhanced-tumor-targeting-selectivity-by-modulating-bispecific-antibody-binding-affinity-and-format-valence
#3
Yariv Mazor, Kris F Sachsenmeier, Chunning Yang, Anna Hansen, Jessica Filderman, Kathy Mulgrew, Herren Wu, William F Dall'Acqua
Bispecific antibodies are considered attractive bio-therapeutic agents owing to their ability to target two distinct disease mediators. Cross-arm avidity targeting of antigen double-positive cancer cells over single-positive normal tissue is believed to enhance the therapeutic efficacy, restrict major escape mechanisms and increase tumor-targeting selectivity, leading to reduced systemic toxicity and improved therapeutic index. However, the interplay of factors regulating target selectivity is not well understood and often overlooked when developing clinically relevant bispecific therapeutics...
January 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28044228/reduced-il-37-production-increases-spontaneous-chemokine-expressions-in-colon-epithelial-cells
#4
Sezin Günaltay, Mohammed Ghiboub, Olof Hultgren, Elisabeth Hultgren Hörnquist
BACKGROUND AND AIM: Microscopic colitis, comprising collagenous colitis and lymphocytic colitis, is a common cause of chronic diarrhea. Previously, we showed enhanced chemokine productions in microscopic colitis patients, indicating dysregulated immune cell chemotaxis in the immunopathogenesis. We also showed decreased mRNA of IL-37, mainly regarded as an anti-inflammatory cytokine, in the colonic mucosa of these patients, potentially an important factor for the chronicity of the colitis...
January 2, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28041849/inhibition-of-crispr-cas9-with-bacteriophage-proteins
#5
Benjamin J Rauch, Melanie R Silvis, Judd F Hultquist, Christopher S Waters, Michael J McGregor, Nevan J Krogan, Joseph Bondy-Denomy
Bacterial CRISPR-Cas systems utilize sequence-specific RNA-guided nucleases to defend against bacteriophage infection. As a countermeasure, numerous phages are known that produce proteins to block the function of class 1 CRISPR-Cas systems. However, currently no proteins are known to inhibit the widely used class 2 CRISPR-Cas9 system. To find these inhibitors, we searched cas9-containing bacterial genomes for the co-existence of a CRISPR spacer and its target, a potential indicator for CRISPR inhibition. This analysis led to the discovery of four unique type II-A CRISPR-Cas9 inhibitor proteins encoded by Listeria monocytogenes prophages...
January 12, 2017: Cell
https://www.readbyqxmd.com/read/27984732/perturb-seq-dissecting-molecular-circuits-with-scalable-single-cell-rna-profiling-of-pooled-genetic-screens
#6
Atray Dixit, Oren Parnas, Biyu Li, Jenny Chen, Charles P Fulco, Livnat Jerby-Arnon, Nemanja D Marjanovic, Danielle Dionne, Tyler Burks, Raktima Raychowdhury, Britt Adamson, Thomas M Norman, Eric S Lander, Jonathan S Weissman, Nir Friedman, Aviv Regev
Genetic screens help infer gene function in mammalian cells, but it has remained difficult to assay complex phenotypes-such as transcriptional profiles-at scale. Here, we develop Perturb-seq, combining single-cell RNA sequencing (RNA-seq) and clustered regularly interspaced short palindromic repeats (CRISPR)-based perturbations to perform many such assays in a pool. We demonstrate Perturb-seq by analyzing 200,000 cells in immune cells and cell lines, focusing on transcription factors regulating the response of dendritic cells to lipopolysaccharide (LPS)...
December 15, 2016: Cell
https://www.readbyqxmd.com/read/27984730/naturally-occurring-off-switches-for-crispr-cas9
#7
April Pawluk, Nadia Amrani, Yan Zhang, Bianca Garcia, Yurima Hidalgo-Reyes, Jooyoung Lee, Alireza Edraki, Megha Shah, Erik J Sontheimer, Karen L Maxwell, Alan R Davidson
CRISPR-Cas9 technology would be enhanced by the ability to inhibit Cas9 function spatially, temporally, or conditionally. Previously, we discovered small proteins encoded by bacteriophages that inhibit the CRISPR-Cas systems of their host bacteria. These "anti-CRISPRs" were specific to type I CRISPR-Cas systems that do not employ the Cas9 protein. We posited that nature would also yield Cas9 inhibitors in response to the evolutionary arms race between bacteriophages and their hosts. Here, we report the discovery of three distinct families of anti-CRISPRs that specifically inhibit the CRISPR-Cas9 system of Neisseria meningitidis...
December 15, 2016: Cell
https://www.readbyqxmd.com/read/27943633/integrated-genome-and-protein-editing-swaps-%C3%AE-2-6-sialylation-for-%C3%AE-2-3-sialic-acid-on-recombinant-antibodies-from-cho
#8
Cheng-Yu Chung, Qiong Wang, Shuang Yang, Bojiao Yin, Hui Zhang, Michael Betenbaugh
Immunoglobin G with α-2,6 sialylation has been reported to have an impact on antibody-depend cellular cytotoxicity and anti-inflammatory efficacy. However, production of antibodies with α-2,6 sialylation from Chinese hamster ovary cells is challenging due to the inaccessibility of sialyltransferases for the heavy chain N-glycan site and the presence of exclusively α-2,3 sialyltransferases. In this study, combining mutations on the Fc regions to allow sialyltransferase accessibility with overexpression of α-2,6 sialyltransferase produced IgG with significant levels of both α-2,6 and α-2,3 sialylation...
December 12, 2016: Biotechnology Journal
https://www.readbyqxmd.com/read/27926730/integrin-yap-taz-jnk-cascade-mediates-atheroprotective-effect-of-unidirectional-shear-flow
#9
Li Wang, Jiang-Yun Luo, Bochuan Li, Xiao Yu Tian, Li-Jing Chen, Yuhong Huang, Jian Liu, Dan Deng, Chi Wai Lau, Song Wan, Ding Ai, King-Lun Kingston Mak, Ka Kui Tong, Kin Ming Kwan, Nanping Wang, Jeng-Jiann Chiu, Yi Zhu, Yu Huang
The Yorkie homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1), effectors of the Hippo pathway, have been identified as mediators for mechanical stimuli. However, the role of YAP/TAZ in haemodynamics-induced mechanotransduction and pathogenesis of atherosclerosis remains unclear. Here we show that endothelial YAP/TAZ activity is regulated by different patterns of blood flow, and YAP/TAZ inhibition suppresses inflammation and retards atherogenesis...
December 7, 2016: Nature
https://www.readbyqxmd.com/read/27896818/coupling-immunity-and-programmed-cell-suicide-in-prokaryotes-life-or-death-choices
#10
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...
January 2017: 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
#11
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
#12
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
#13
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
#14
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...
January 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27806571/knockout-of-the-ribonuclease-inhibitor-gene-leaves-human-cells-vulnerable-to-secretory-ribonucleases
#15
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 antioxidant. Here, we use CRISPR-Cas9 to knock out 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 22, 2016: Biochemistry
https://www.readbyqxmd.com/read/27799325/muts2-promotes-homologous-recombination-in-bacillus-subtilis
#16
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 (MMR) pathway. 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...
January 15, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/27786251/ovariectomy-upregulated-the-expression-of-peroxiredoxin-1-5-in-osteoblasts-of-mice
#17
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
#18
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
#19
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
#20
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
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