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Synthetic lethality

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https://www.readbyqxmd.com/read/28211914/eco-evolutionary-feedbacks-can-rescue-cooperation-in-microbial-populations
#1
Clara Moreno-Fenoll, Matteo Cavaliere, Esteban Martínez-García, Juan F Poyatos
Bacterial populations whose growth depends on the cooperative production of public goods are usually threatened by the rise of cheaters that do not contribute but just consume the common resource. Minimizing cheater invasions appears then as a necessary mechanism to maintain these populations. However, that invasions result instead in the persistence of cooperation is a prospect that has yet remained largely unexplored. Here, we show that the demographic collapse induced by cheaters in the population can actually contribute to the rescue of cooperation, in a clear illustration of how ecology and evolution can influence each other...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28211886/a-novel-approach-for-the-identification-of-efficient-combination-therapies-in-primary-human-acute-myeloid-leukemia-specimens
#2
I Baccelli, J Krosl, G Boucher, I Boivin, V-P Lavallée, J Hébert, S Lemieux, A Marinier, G Sauvageau
Appropriate culture methods for the interrogation of primary leukemic samples were hitherto lacking and current assays for compound screening are not adapted for large-scale investigation of synergistic combinations. In this study, we report a novel approach that efficiently distills synthetic lethal interactions between small molecules active on primary human acute myeloid leukemia (AML) specimens. In single-dose experiments and under culture conditions preserving leukemia stem cell activity, our strategy considerably reduces the number of tests needed for the identification of promising compound combinations...
February 17, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28206865/assessment-of-a-simple-compound-saving-method-to-study-insecticidal-activity-of-natural-extracts-and-pure-compounds-against-mosquito-larvae
#3
Michaël Falkowski, Arnaud Jahn-Oyac, Emma Ferrero, Jean Issaly, Véronique Eparvier, Romain Girod, Alice M S Rodrigues, Didier Stien, Emeline Houël, Isabelle Dusfour
Research on natural insecticides has intensified with the spread of resistance to chemicals among insects, particularly disease vectors. To evaluate compounds, the World Health Organization (WHO) has published standardized procedures. However, those may be excessively compound-consuming when it comes to assessing the activity of natural extracts and pure compounds isolated in limited amount. As part of our work on the discovery of new mosquito larvicides from Amazonian plants, we developed a compound-saving assay in 5-ml glass tubes instead of WHO larval 100-ml cups...
December 2016: Journal of the American Mosquito Control Association
https://www.readbyqxmd.com/read/28193780/an-essential-gene-dataset-defines-functional-gene-networks
#4
(no author information available yet)
Gene essentiality pattern analysis can identify gene interactions and synthetic lethal interactions.
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28182330/heat-shock-protein-27-hsp27-hspb1-is-synthetic-lethal-to-cells-with-oncogenic-activation-of-met-egfr-and-braf
#5
John David Konda, Martina Olivero, Daniele Musiani, Simona Lamba, Maria Flavia Di Renzo
The small Heat Shock Protein of 27 KDa (HSP27) is highly expressed in many cancers and is associated with aggressive tumor behaviour, metastasis, poor prognosis and resistance to chemotherapy. We aimed at assessing the role of HSP27 in modulating responses to target therapies. We selected several oncogene-addicted cancer cell lines, which undergo either cell cycle blockade or cell death in response to agents that target the specific oncogene. Surprisingly, HSP27 suppression alone resulted in the apoptotic death of MET-addicted EBC-1 lung cancer cells, EGFR-addicted colorectal carcinoma DiFi cells and BRAF-addicted colorectal carcinoma COLO205 and OXCO-1 and melanoma COLO741 cells, all of which also undergo death when treated with the specific targeted agent...
February 9, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28179288/aurora-b-inhibitor-tak-901-synergizes-with-bcl-xl-inhibition-by-inducing-active-bax-in-cancer-cells
#6
Saomi Murai, Jennifer Matuszkiewicz, Yuumi Okuzono, Hiroyuki Miya, Ron DE Jong
BACKGROUND: Aurora B kinase plays an essential role in chromosome segregation and cytokinesis, and is dysregulated in many cancer types, making it an attractive therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy in both in vitro and in vivo oncology models. MATERIALS AND METHODS: We conducted a synthetic lethal siRNA screening to identify the genes that, when silenced, can potentiate the cell growth-inhibitory effect of TAK-901. RESULTS: B-cell lymphoma-extra large (BCL-xL) depletion by siRNA or chemical inhibition synergized with TAK-901 in cancer cell lines...
2017: Anticancer Research
https://www.readbyqxmd.com/read/28176646/epigenetic-regulation-of-emt-in-non-small-cell-lung-cancer
#7
Karen O'Leary, Alice Shia, Peter Schmid
Lung cancer remains the most diagnosed cancer in the world, with a high mortality rate and fewer therapeutic options. The most common lung cancer is non-small cell, which can consist of adenocarcinoma, squamous cell carcinoma and large cell lung carcinoma. As per all solid tumours, the changes that occur for the initiation and metastasis of lung cancer can be described using the EMT (epithelial mesenchymal transition). Cells progressing through EMT lose their epithelial cell characteristics, expressing more mesenchymal markers and are phenotypically different...
February 3, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28174120/xenobiotics-and-the-glucocorticoid-receptor
#8
REVIEW
Linda S M Gulliver
Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes...
February 4, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28173629/enhanced-dependency-of-kras-mutant-colorectal-cancer-cells-on-rad51-dependent-homologous-recombination-repair-identified-from-genetic-interactions-in-saccharomyces-cerevisiae
#9
Murugan Kalimutho, Amanda L Bain, Bipasha Mukherjee, Purba Nag, Devathri M Nanayakkara, Sarah K Harten, Janelle L Harris, Goutham Narayanan Subramanian, Debottam Sinha, Senji Shirasawa, Sriganesh Srihari, Sandeep Burma, Kum Kum Khanna
Activating KRAS mutations drive colorectal cancer tumorigenesis and influence response to anti-EGFR targeted therapy. Despite recent advances in understanding Ras signaling biology and the revolution in therapies for melanoma using BRAF inhibitors, no targeted agents have been effective in KRAS mutant cancers, mainly due to activation of compensatory pathways. Here, by leveraging the largest synthetic lethal genetic interactome in yeast, we identify that KRAS-mutated colorectal cancer cells have augmented homologous recombination repair (HRR) signaling...
February 7, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28167505/acquired-resistance-to-the-hsp90-inhibitor-ganetespib-in-kras-mutant-nsclc-is-mediated-via-reactivation-of-the-erk-p90rsk-mtor-signaling-network
#10
Suman Chatterjee, Eric H-B Huang, Ian Christie, Brenda F Kurland, Timothy F Burns
Approximately 25% of non-small cell lung cancer (NSCLC) patients have KRAS mutations and no effective therapeutic strategy exists for these patients. The use of Heat shock protein 90 (Hsp90) inhibitors in KRAS mutant NSCLC appeared to be a promising approach since these inhibitors target many KRAS downstream effectors, however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations which may prevent and overcome resistance to Hsp90 inhibitors...
February 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28166733/a-machine-learning-classifier-trained-on-cancer-transcriptomes-detects-nf1-inactivation-signal-in-glioblastoma
#11
Gregory P Way, Robert J Allaway, Stephanie J Bouley, Camilo E Fadul, Yolanda Sanchez, Casey S Greene
BACKGROUND: We have identified molecules that exhibit synthetic lethality in cells with loss of the neurofibromin 1 (NF1) tumor suppressor gene. However, recognizing tumors that have inactivation of the NF1 tumor suppressor function is challenging because the loss may occur via mechanisms that do not involve mutation of the genomic locus. Degradation of the NF1 protein, independent of NF1 mutation status, phenocopies inactivating mutations to drive tumors in human glioma cell lines. NF1 inactivation may alter the transcriptional landscape of a tumor and allow a machine learning classifier to detect which tumors will benefit from synthetic lethal molecules...
February 6, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28166537/synthetic-essentiality-of-chromatin-remodelling-factor-chd1-in-pten-deficient-cancer
#12
Di Zhao, Xin Lu, Guocan Wang, Zhengdao Lan, Wenting Liao, Jun Li, Xin Liang, Jasper Robin Chen, Sagar Shah, Xiaoying Shang, Ming Tang, Pingna Deng, Prasenjit Dey, Deepavali Chakravarti, Peiwen Chen, Denise J Spring, Nora M Navone, Patricia Troncoso, Jianhua Zhang, Y Alan Wang, Ronald A DePinho
Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions. Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify 'synthetic-essential' genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency...
February 6, 2017: Nature
https://www.readbyqxmd.com/read/28162770/gene-essentiality-profiling-reveals-gene-networks-and-synthetic-lethal-interactions-with-oncogenic-ras
#13
Tim Wang, Haiyan Yu, Nicholas W Hughes, Bingxu Liu, Arek Kendirli, Klara Klein, Walter W Chen, Eric S Lander, David M Sabatini
The genetic dependencies of human cancers widely vary. Here, we catalog this heterogeneity and use it to identify functional gene interactions and genotype-dependent liabilities in cancer. By using genome-wide CRISPR-based screens, we generate a gene essentiality dataset across 14 human acute myeloid leukemia (AML) cell lines. Sets of genes with correlated patterns of essentiality across the lines reveal new gene relationships, the essential substrates of enzymes, and the molecular functions of uncharacterized proteins...
February 1, 2017: Cell
https://www.readbyqxmd.com/read/28154181/usp39-deubiquitinase-is-essential-for-kras-driven-cancer
#14
Julia M Fraile, Eusebio Manchado, Amaia Lujambio, Victor Quesada, Diana Campos-Iglesias, Thomas Webb, Scott W Lowe, Carlos Lopez-Otin, Jose M P Freije
KRAS is the most frequently mutated oncogene in human cancer, but its therapeutic targeting remains challenging. Here, we report a synthetic lethal screen with a library of deubiquitinases and identify USP39, which encodes an essential splicing factor, as a critical gene for the viability of KRAS-dependent cells. We show that splicing fidelity inhibitors decrease preferentially the proliferation rate of KRAS-active cells. Moreover, depletion of DHX38, encoding an USP39-interacting splicing factor, also reduces the viability of these cells...
February 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28153092/gm-csf-and-il-4-fusion-cytokine-induces-b-cell-dependent-hematopoietic-regeneration
#15
Jiusheng Deng, Yanqiu Li, Andrea Pennati, Shala Yuan, Jian Hui Wu, Edmund K Waller, Jacques Galipeau
Hematopoietic stem cells (HSCs) have the capacity to self-renew and differentiate into hematopoietic cells and have been utilized to replace diseased bone marrow for patients with cancers and blood disorders. Although remarkable progress has been made in developing new tools to manipulate HSCs for clinic use, there is still no effective method to expand HSCs in vivo for quick repopulation of hematopoietic cells following sublethal irradiation. We have recently described a novel synthetic cytokine that is derived from the fusion of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4; named as GIFT4), and we have now discovered that GIFT4 fusokine promotes long-term hematopoietic regeneration in a B cell-dependent manner...
February 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28152405/evaluation-of-larvicidal-activity-and-ecotoxicity-of-linalool-methyl-cinnamate-and-methyl-cinnamate-linalool-in-combination-against-aedes-aegypti
#16
Gislene M Fujiwara, Vinícius Annies, Camila F de Oliveira, Ricardo A Lara, Maria M Gabriel, Fernando C M Betim, Jéssica M Nadal, Paulo V Farago, Josiane F G Dias, Obdulio G Miguel, Marilis D Miguel, Francisco A Marques, Sandra M W Zanin
The frequent use of synthetic pesticides to control Aedes aegypti population can lead to environmental and/or human contamination and the emergence of resistant insects. Linalool and methyl cinnamate are presented as an alternative to the synthetic pesticides, since they can exhibit larvicidal, repellent and/or insecticidal activity and are considered safe for use. The aim of this study was to evaluate the larvicidal activity of methyl cinnamate, linalool and methyl cinnamate/linalool in combination (MC-L) (1:4 ratio, respectively) against Aedes aegypti...
January 30, 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/28143806/efficient-eradication-of-established-tumors-in-mice-with-cationic-liposome-based-synthetic-long-peptide-vaccines
#17
Eleni Maria Varypataki, Naomi Benne, Joke Bouwstra, Wim Jiskoot, Ferry Ossendorp
Therapeutic vaccination with synthetic long peptides (SLPs) can be clinically effective against HPV-induced pre-malignant lesions; however, their efficiency in established malignant lesions leaves room for improvement. Here, we report the high therapeutic potency of cationic liposomes loaded with well-defined tumor-specific SLPs and a TLR3 ligand as adjuvant. The cationic particles, with an average size of 160 nm, could strongly activate functional, antigen-specific, CD8(+) and CD4(+) T cells and induced in vivo cytotoxicity against target cells after intradermal vaccination...
January 31, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28138868/combination-treatment-using-ddx3-and-parp-inhibitors-induces-synthetic-lethality-in-brca1-proficient-breast-cancer
#18
Marise R Heerma van Voss, Justin D Brilliant, Farhad Vesuna, Guus M Bol, Elsken van der Wall, Paul J van Diest, Venu Raman
Triple-negative breast cancers have unfavorable outcomes due to their inherent aggressive behavior and lack of targeted therapies. Breast cancers occurring in BRCA1 mutation carriers are mostly triple-negative and harbor homologous recombination deficiency, sensitizing them to inhibition of a second DNA damage repair pathway by, e.g., PARP inhibitors. Unfortunately, resistance against PARP inhibitors in BRCA1-deficient cancers is common and sensitivity is limited in BRCA1-proficient breast cancers. RK-33, an inhibitor of the RNA helicase DDX3, was previously demonstrated to impede non-homologous end-joining repair of DNA breaks...
March 2017: Medical Oncology
https://www.readbyqxmd.com/read/28138034/azd6738-a-novel-oral-inhibitor-of-atr-induces-synthetic-lethality-with-atm-deficiency-in-gastric-cancer-cells
#19
Ahrum Min, Seock-Ah Im, Hyemin Jang, Seongyeong Kim, Miso Lee, Debora Keunyoung Kim, Yaewon Yang, Hee-Jun Kim, Kyung-Hun Lee, Jin Won Kim, Tae-Yong Kim, Do-Youn Oh, Jeff Brown, Alan Lau, Mark J O Connor, Yung-Jue Bang
Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect (HRD). The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer. In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28132844/active-interaction-mapping-reveals-the-hierarchical-organization-of-autophagy
#20
Michael H Kramer, Jean-Claude Farré, Koyel Mitra, Michael Ku Yu, Keiichiro Ono, Barry Demchak, Katherine Licon, Mitchell Flagg, Rama Balakrishnan, J Michael Cherry, Suresh Subramani, Trey Ideker
We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces, captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions...
January 23, 2017: Molecular Cell
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