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CRISPR/Cas9 cell death

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https://www.readbyqxmd.com/read/29435173/crispr-knock-out-of-programmed-cell-death-protein-1-enhances-anti-tumor-activity-of-cytotoxic-t-lymphocytes
#1
Zhilong Zhao, Long Shi, Wei Zhang, Jinsheng Han, Shaohui Zhang, Zexian Fu, Jianhui Cai
Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that functions to attenuate T cell activation. In this study, we knocked out (KO) PD-1 in cytotoxic T lymphocytes (CTLs) using CRISPR-Cas9 system to evaluate its effect on the anti-tumor activity of the CTLs against multiple myeloma (MM). Results show that PD-1 KO CTLs facilitate apoptosis and caspase activation of the co-cultured MM cells and enhanced MM cell death by 36% compared with the control. PD-1 KO also increased TNF-α and IFN-γ secretion of the CTLs by 2...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29378335/mitochondrial-rescue-prevents-glutathione-peroxidase-dependent-ferroptosis
#2
Anja Jelinek, Lukas Heyder, Michael Daude, Matthias Plessner, Sylvia Krippner, Robert Grosse, Wibke E Diederich, Carsten Culmsee
Research into oxidative cell death is producing exciting new mechanisms, such as ferroptosis, in the neuropathologies of cerebral ischemia and hemorrhagic brain insults. Ferroptosis is an oxidative form of regulated necrotic cell death featuring glutathione (GSH) depletion, disrupted glutathione peroxidase-4 (GPX4) redox defense and detrimental lipid reactive oxygen species (ROS) formation. Further, our recent findings identified mitochondrial damage in models of oxidative glutamate toxicity, glutathione peroxidase depletion, and ferroptosis...
January 26, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29358305/cerebral-organoids-derived-from-sandhoff-disease-induced-pluripotent-stem-cells-exhibit-impaired-neurodifferentiation
#3
Maria L Allende, Emily K Cook, Bridget C Larman, Adrienne Nugent, Jacqueline M Brady, Diane Golebiowski, Miguel Sena-Esteves, Cynthia J Tifft, Richard L Proia
Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of beta-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes...
January 22, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29346757/p53-suppresses-metabolic-stress-induced-ferroptosis-in-cancer-cells
#4
Amy Tarangelo, Leslie Magtanong, Kathryn T Bieging-Rolett, Yang Li, Jiangbin Ye, Laura D Attardi, Scott J Dixon
How cancer cells respond to nutrient deprivation remains poorly understood. In certain cancer cells, deprivation of cystine induces a non-apoptotic, iron-dependent form of cell death termed ferroptosis. Recent evidence suggests that ferroptosis sensitivity may be modulated by the stress-responsive transcription factor and canonical tumor suppressor protein p53. Using CRISPR/Cas9 genome editing, small-molecule probes, and high-resolution, time-lapse imaging, we find that stabilization of wild-type p53 delays the onset of ferroptosis in response to cystine deprivation...
January 16, 2018: Cell Reports
https://www.readbyqxmd.com/read/29278415/towards-industrial-production-of-isoprenoids-in-escherichia-coli-lessons-learned-from-crispr-cas9-based-optimization-of-a-chromosomally-integrated-mevalonate-pathway
#5
Jorge Alonso-Gutierrez, Daisuke Koma, Qijun Hu, Yuchen Yang, Leanne Jade G Chan, Christopher J Petzold, Paul D Adams, Claudia E Vickers, Lars K Nielsen, Jay D Keasling, Taek Soon Lee
Escherichia coli has been the organism of choice for the production of different chemicals by engineering native and heterologous pathways. In the present study, we simultaneously address some of the main issues associated with E. coli as an industrial platform for isoprenoids, including an inability to grow on sucrose, a lack of endogenous control over toxic mevalonate (MVA) pathway intermediates, and the limited pathway engineering into the chromosome. As a proof of concept, we generated an E. coli DH1 strain able to produce the isoprenoid bisabolene from sucrose by integrating the cscAKB operon into the chromosome and by expressing a heterologous MVA pathway under stress-responsive control...
December 26, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29242562/ros-induced-cleavage-of-nhlrc2-by-caspase-8-leads-to-apoptotic-cell-death-in-the-hct116-human-colon-cancer-cell-line
#6
Kensuke Nishi, Yuri Iwaihara, Toshiyuki Tsunoda, Keiko Doi, Toshifumi Sakata, Senji Shirasawa, Shuhei Ishikura
Excess production of reactive oxygen species (ROS) is known to cause apoptotic cell death. However, the molecular mechanisms whereby ROS induce apoptosis remain elusive. Here we show that the NHL-repeat-containing protein 2 (NHLRC2) thioredoxin-like domain protein is cleaved by caspase-8 in ROS-induced apoptosis in the HCT116 human colon cancer cell line. Treatment of HCT116 cells with the oxidant tert-butyl hydroperoxide (tBHP) induced apoptosis and reduced NHLRC2 protein levels, whereas pretreatment with the antioxidant N-acetyl-L-cysteine prevented apoptosis and the decrease in NHLRC2 protein levels seen in tBHP-treated cells...
December 14, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29238045/ripk3-promotes-adenovirus-type-5-activity
#7
Melanie Weigert, Alex Binks, Suzanne Dowson, Elaine Y L Leung, Dmitris Athineos, Xinzi Yu, Margaret Mullin, Josephine B Walton, Clare Orange, Darren Ennis, Karen Blyth, Stephen W G Tait, Iain A McNeish
Oncolytic adenoviral mutants infect human malignant cells and replicate selectively within them. This induces direct cytotoxicity that can also trigger profound innate and adaptive immune responses. However, the mechanism by which adenoviruses produce cell death remains uncertain. We previously suggested that type 5 adenoviruses, including the E1A CR2 deletion mutant dl922-947, might induce a novel form of programmed death resembling necroptosis. Here we have investigated the roles of core necrosis proteins RIPK1, RIPK3 and MLKL in the cytotoxicity of dl922-947 and other adenovirus serotypes...
December 13, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29236701/anti-leukemic-activity-of-bortezomib-and-carfilzomib-on-b-cell-precursor-all-cell-lines
#8
Kazuya Takahashi, Takeshi Inukai, Toshihiko Imamura, Mio Yano, Chihiro Tomoyasu, David M Lucas, Atsushi Nemoto, Hiroki Sato, Meixian Huang, Masako Abe, Keiko Kagami, Tamao Shinohara, Atsushi Watanabe, Shinpei Somazu, Hiroko Oshiro, Koshi Akahane, Kumiko Goi, Jiro Kikuchi, Yusuke Furukawa, Hiroaki Goto, Masayoshi Minegishi, Shotaro Iwamoto, Kanji Sugita
Prognosis of childhood acute lymphoblastic leukemia (ALL) has been dramatically improved. However, prognosis of the cases refractory to primary therapy is still poor. Recent phase 2 study on the efficacy of combination chemotherapy with bortezomib (BTZ), a proteasome inhibitor, for refractory childhood ALL demonstrated favorable clinical outcomes. However, septic death was observed in over 10% of patients, indicating the necessity of biomarkers that could predict BTZ sensitivity. We investigated in vitro BTZ sensitivity in a large panel of ALL cell lines that acted as a model system for refractory ALL, and found that Philadelphia chromosome-positive (Ph+) ALL, IKZF1 deletion, and biallelic loss of CDKN2A were associated with favorable response...
2017: PloS One
https://www.readbyqxmd.com/read/29222162/dual-inhibition-of-pik3c3-and-fgfr-as-a-new-therapeutic-approach-to-treat-bladder-cancer
#9
Chun-Han Chen, C Changou, Tsung-Han Hsieh, Yu-Ching Lee, Cheng-Ying Chu, Kai-Cheng Hsu, Hao-Ching Wang, Yu-Chen Lin, Yan-Ni Lo, Yun-Ru Liu, Jing-Ping Liou, Yun Yen
PURPOSE: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms. EXPERIMENTAL DESIGN: Autophagy flux, morphology and intracellular organelles were evaluated by western blotting, transmission electron microscope and fluorescence microscope. Molecular docking, surface plasmon resonance assay were performed to identify drug-protein interaction...
December 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29221169/targeting-pp2a-activates-ampk-signaling-to-inhibit-colorectal-cancer-cells
#10
Cuiping Dai, Xuning Zhang, Da Xie, Peipei Tang, Chunmei Li, Yi Zuo, Baofei Jiang, Caiping Xue
LB-100 is a novel PP2A inhibitor. Its activity in human colorectal cancer (CRC) cells was tested. The in vitro studies demonstrated that LB-100 inhibited survival and proliferation of both established CRC cells (HCT-116 and HT-29 lines) and primary human colon cancer cells. Further, LB-100 activated apoptosis and induced G1-S cell cycle arrest in CRC cells. LB-100 inhibited PP2A activity and activated AMPK signaling in CRC cells. AMPKα1 dominant negative mutation, shRNA-mediated knockdown or complete knockout (by CRISPR/Cas9 method) largely attenuated LB-100-induced AMPK activation and HCT-116 cytotoxicity...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29217433/hypertrophic-cardiomyopathy-linked-mutation-in-troponin-t-causes-myofibrillar-disarray-and-pro-arrhythmic-action-potential-changes-in-human-ipsc-cardiomyocytes
#11
Lili Wang, Kyungsoo Kim, Shan Parikh, Adrian Gabriel Cadar, Kevin R Bersell, Huan He, Jose R Pinto, Dmytro O Kryshtal, Bjorn C Knollmann
BACKGROUND: Mutations in cardiac troponin T (TnT) are linked to increased risk of ventricular arrhythmia and sudden death despite causing little to no cardiac hypertrophy. Studies in mice suggest that the hypertrophic cardiomyopathy (HCM)-associated TnT-I79N mutation increases myofilament Ca sensitivity and is arrhythmogenic, but whether findings from mice translate to human cardiomyocyte electrophysiology is not known. OBJECTIVES: To study the effects of the TnT-I79N mutation in human cardiomyocytes...
December 4, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29193607/comparative-genomics-reveals-that-loss-of-lunatic-fringe-lfng-promotes-melanoma-metastasis
#12
Martin Del Castillo Velasco-Herrera, Louise van der Weyden, Jeremie Nsengimana, Anneliese O Speak, Marcela K Sjöberg, D Timothy Bishop, Göran Jönsson, Julia Newton-Bishop, David J Adams
Metastasis is the leading cause of death in patients with advanced melanoma, yet the somatic alterations that aid tumour cell dissemination and colonization are poorly understood. Here, we deploy comparative genomics to identify and validate clinically relevant drivers of melanoma metastasis. To do this we identified a set of 976 genes whose expression level was associated with a poor outcome in patients from two large melanoma cohorts. Next, we characterised the genomes and transcriptomes of mouse melanoma cell lines defined as weakly metastatic, and their highly metastatic derivatives...
November 29, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/29184850/internalization-of-the-active-subunit-of-the-aggregatibacter-actinomycetemcomitans-cytolethal-distending-toxin-is-dependent-upon-cellugyrin-synaptogyrin-2-a-host-cell-non-neuronal-paralog-of-the-synaptic-vesicle-protein-synaptogyrin-1
#13
Kathleen Boesze-Battaglia, Lisa P Walker, Anuradha Dhingra, Konstantin Kandror, Hsin-Yao Tang, Bruce J Shenker
The Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) is a heterotrimeric AB2 toxin capable of inducing lymphocytes, and other cell types, to undergo cell cycle arrest and apoptosis. Exposure to Cdt results in binding to the cell surface followed by internalization and translocation of the active subunit, CdtB, to intracellular compartments. These events are dependent upon toxin binding to cholesterol in the context of lipid rich membrane microdomains often referred to as lipid rafts. We now demonstrate that, in addition to binding to the plasma membrane of lymphocytes, another early and critical event initiated by Cdt is the translocation of the host cell protein, cellugyrin (synaptogyrin-2) to the same cholesterol-rich microdomains...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29183726/gsdme-mediates-caspase-3-dependent-pyroptosis-in-gastric-cancer
#14
Yubin Wang, Bo Yin, Dinuo Li, Guijun Wang, Xiangdong Han, Xuejun Sun
Gastric cancer is a malignancy that starts from the cells in the stomach with relatively low overall survival rate. Chemotherapy following resection surgery has been recommended as a curative strategy for gastric cancer. However, the mechanism of the chemotherapy drugs on gastric cancer is not completely understood. Pyroptosis is a form of programmed cell death and plays critical role in immunity. The role of pyroptosis on cancer cells is less known. In this study, we treated SGC-7901 and MKN-45 with 5-FU and found that the cell viability was significantly decreased...
November 25, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29178829/encore-an-efficient-software-for-crispr-screens-identifies-new-players-in-extrinsic-apoptosis
#15
Dietrich Trümbach, Susanne Pfeiffer, Manuel Poppe, Hagen Scherb, Sebastian Doll, Wolfgang Wurst, Joel A Schick
BACKGROUND: As CRISPR/Cas9 mediated screens with pooled guide libraries in somatic cells become increasingly established, an unmet need for rapid and accurate companion informatics tools has emerged. We have developed a lightweight and efficient software to easily manipulate large raw next generation sequencing datasets derived from such screens into informative relational context with graphical support. The advantages of the software entitled ENCoRE (Easy NGS-to-Gene CRISPR REsults) include a simple graphical workflow, platform independence, local and fast multithreaded processing, data pre-processing and gene mapping with custom library import...
November 25, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29175330/activation-of-amp-activated-protein-kinase-by-compound-991-protects-osteoblasts-from-dexamethasone
#16
Yong-Yi Xu, Feng-Li Chen, Feng Ji, Hao-Dong Fei, Yue Xie, Shou-Guo Wang
Dexamethasone (Dex) induces direct cytotoxicity to cultured osteoblasts. The benzimidazole derivative compound 991 ("C991") is a novel and highly-efficient AMP-activated protein kinase (AMPK) activator. Here, in both MC3T3-E1 osteoblastic cells and primary murine osteoblasts, treatment with C991 activated AMPK signaling, and significantly attenuated Dex-induced apoptotic and non-apoptotic cell death. AMPKα1 knockdown (by shRNA), complete knockout (by CRISPR/Cas9 method) or dominant negative mutation (T172A) not only blocked C991-mediated AMPK activation, but also abolished its pro-survival effect against Dex in osteoblasts...
November 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29167274/distinct-cellular-mechanisms-underlie-smooth-muscle-turnover-in-vascular-development-and-repair
#17
Urmas Roostalu, Bashar Aldeiri, Alessandra Albertini, Neil E Humphreys, Maj Simonsen-Jackson, Jason K Wong, Giulio Cossu
Rationale: Vascular smooth muscle turnover has important implications for blood vessel repair and for the development of cardiovascular diseases, yet lack of specific transgenic animal models has prevented it's in vivo analysis. Objective: To characterize the dynamics and mechanisms of vascular smooth muscle turnover from the earliest stages of embryonic development to arterial repair in the adult. Methods and Results: We show that CD146 is transiently expressed in vascular smooth muscle development. By using CRISPR-Cas9 genome editing and in vitro smooth muscle differentiation assay we demonstrate that CD146 regulates the balance between proliferation and differentiation...
November 22, 2017: Circulation Research
https://www.readbyqxmd.com/read/29163048/nicotinic-acetylcholine-receptor-subtype-alpha-9-mediates-triple-negative-breast-cancers-based-on-a-spontaneous-pulmonary-metastasis-mouse-model
#18
Li-Chi Huang, Ching-Ling Lin, Jia-Zheng Qiu, Chun-Yu Lin, Kai-Wen Hsu, Ka-Wai Tam, Jung-Yu Lee, Jinn-Moon Yang, Chia-Hwa Lee
Triple-negative breast cancer (TNBC) subtype is associated with poor prognosis and a high risk of recurrence-related death in women. Despite the aggressiveness of TNBCs, targeted TNBC therapy is not yet available in the clinic. To overcome this challenge, we generated highly metastatic TNBC cells (LM) derived from metastasized lung cells via a serial spontaneous pulmonary metastasis animal model to identify targetable molecules for attenuating the progression of TNBC metastasis. Gene analysis of primary tumor (P), first-round (1LM) and second-round (2LM) metastasized lung cells revealed that mesenchymal-related genes were significantly expressed in LM cells, especially in 2LM cells...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29112685/serum-squamous-cell-carcinoma-antigen-as-an-early-indicator-of-response-during-therapy-of-cervical-cancer
#19
Stephanie Markovina, Songyan Wang, Lauren E Henke, Cliff J Luke, Stephen C Pak, Todd DeWees, John D Pfeifer, Julie K Schwarz, Weijun Liu, Shuai Chen, David Mutch, Xiaowei Wang, Matthew A Powell, Barry A Siegel, Farrokh Dehdashti, Gary A Silverman, Perry W Grigsby
BACKGROUND: Pretreatment serum squamous cell carcinoma antigen (SCCA) is a prognostic biomarker in women with cervical cancer. SCCA has not been evaluated as an early indicator of response to chemoradiation therapy (CRT). The molecular role of the two SCCA isoforms, SCCA1 (SERPINB3) and SCCA2 (SERPINB4), in cervical cancer is unknown. We hypothesised that changes in serum SCCA during definitive CRT predicts treatment response, and that SCCA1 mediates radiation resistance. METHODS: Patients treated with definitive CRT for cervical squamous carcinoma with serum SCCA measured were included...
November 7, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29109113/generation-and-characterization-of-sult4a1-mutant-mouse-models
#20
Patrick L Garcia, Mohammed I Hossain, Shaida A Andrabi, Charles N Falany
Sulfotransferase 4A1 (SULT4A1) belongs to the cytosolic sulfotransferase (SULT) superfamily of enzymes that catalyze sulfonation reactions with a variety of endogenous and exogenous substrates. Of the SULTs, SULT4A1 was shown to have the highest sequence homology between vertebrate species, yet no known function or enzymatic activity have been identified for this orphan SULT. To better understand SULT4A1 function in mammalian brain, two mutant SULT4A1 mouse strains were generated utilizing CRISPR-Cas9 technology...
November 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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