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Synthetic lethality

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https://www.readbyqxmd.com/read/28330500/larvicidal-activity-of-phytosteroid-compounds-from-leaf-extract-of-solanum-nigrum-against-culex-vishnui-group-and-anopheles-subpictus
#1
Anjali Rawani, Anushree Singha Ray, Anupam Ghosh, Mary Sakar, Goutam Chandra
BACKGROUND: Vector control is facing a menace due to the appearance of resistance to synthetic insecticides. Insecticides of plant origin may provide appropriate substitute biocontrol techniques in the future. The present study was carried out to investigate the bio control potentiality of active ingredient isolated from chloroform: methanol (1:1 v/v) extract of mature leaves of Solanum nigrum L. (Solanaceae) against early 3rd instar larvae of Culex vishnui group (comprising of Cx. vishnui Theobald, Cx...
March 23, 2017: BMC Research Notes
https://www.readbyqxmd.com/read/28327556/control-of-structure-specific-endonucleases-to-maintain-genome-stability
#2
REVIEW
Pierre-Marie Dehé, Pierre Henri L Gaillard
Structure-specific endonucleases (SSEs) have key roles in DNA replication, recombination and repair, and emerging roles in transcription. These enzymes have specificity for DNA secondary structure rather than for sequence, and therefore their activity must be precisely controlled to ensure genome stability. In this Review, we discuss how SSEs are controlled as part of genome maintenance pathways in eukaryotes, with an emphasis on the elaborate mechanisms that regulate the members of the major SSE families - including the xeroderma pigmentosum group F-complementing protein (XPF) and MMS and UV-sensitive protein 81 (MUS81)-dependent nucleases, and the flap endonuclease 1 (FEN1), XPG and XPG-like endonuclease 1 (GEN1) enzymes - during processes such as DNA adduct repair, Holliday junction processing and replication stress...
March 22, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28322442/systems-analysis-of-dynamic-transcription-factor-activity-identifies-targets-for-treatment-in-olaparib-resistant-cancer-cells
#3
Joseph T Decker, Eric C Hobson, Yining Zhang, Seungjin Shin, Alexandra L Thomas, Jacqueline S Jeruss, Kelly B Arnold, Lonnie D Shea
The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly (ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells...
March 21, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28320831/interference-of-the-t-cell-and-antigen-presenting-cell-costimulatory-pathway-using-ctla4-ig-abatacept-prevents-staphylococcal-enterotoxin-b-pathology
#4
Sarah J C Whitfield, Chris Taylor, Jane E Risdall, Gareth D Griffiths, James T A Jones, E Diane Williamson, Sjoerd Rijpkema, Luisa Saraiva, Sandrine Vessillier, A Christopher Green, Alun J Carter
Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that binds the receptors in the APC/T cell synapse and causes increased proliferation of T cells and a cytokine storm syndrome in vivo. Exposure to the toxin can be lethal and cause significant pathology in humans. The lack of effective therapies for SEB exposure remains an area of concern, particularly in scenarios of acute mass casualties. We hypothesized that blockade of the T cell costimulatory signal by the CTLA4-Ig synthetic protein (abatacept) could prevent SEB-dependent pathology...
March 20, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28319113/combinatorial-crispr-cas9-screens-for-de-novo-mapping-of-genetic-interactions
#5
John Paul Shen, Dongxin Zhao, Roman Sasik, Jens Luebeck, Amanda Birmingham, Ana Bojorquez-Gomez, Katherine Licon, Kristin Klepper, Daniel Pekin, Alex N Beckett, Kyle Salinas Sanchez, Alex Thomas, Chih-Chung Kuo, Dan Du, Assen Roguev, Nathan E Lewis, Aaron N Chang, Jason F Kreisberg, Nevan Krogan, Lei Qi, Trey Ideker, Prashant Mali
We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies...
March 20, 2017: Nature Methods
https://www.readbyqxmd.com/read/28319085/synergistic-drug-combinations-for-cancer-identified-in-a-crispr-screen-for-pairwise-genetic-interactions
#6
Kyuho Han, Edwin E Jeng, Gaelen T Hess, David W Morgens, Amy Li, Michael C Bassik
Identification of effective combination therapies is critical to address the emergence of drug-resistant cancers, but direct screening of all possible drug combinations is infeasible. Here we introduce a CRISPR-based double knockout (CDKO) system that improves the efficiency of combinatorial genetic screening using an effective strategy for cloning and sequencing paired single guide RNA (sgRNA) libraries and a robust statistical scoring method for calculating genetic interactions (GIs) from CRISPR-deleted gene pairs...
March 20, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28317934/dek-is-required-for-homologous-recombination-repair-of-dna-breaks
#7
Eric A Smith, Boris Gole, Nicholas A Willis, Rebeca Soria, Linda M Starnes, Eric F Krumpelbeck, Anil G Jegga, Abdullah M Ali, Haihong Guo, Amom R Meetei, Paul R Andreassen, Ferdinand Kappes, Lisa M Privette Vinnedge, Jeremy A Daniel, Ralph Scully, Lisa Wiesmüller, Susanne I Wells
DEK is a highly conserved chromatin-bound protein whose upregulation across cancer types correlates with genotoxic therapy resistance. Loss of DEK induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair. While these DEK-deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout mice...
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302823/parp-inhibitors-synthetic-lethality-in-the-clinic
#8
REVIEW
Christopher J Lord, Alan Ashworth
PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease...
March 17, 2017: Science
https://www.readbyqxmd.com/read/28299955/niraparib-for-the-treatment-of-ovarian-cancer
#9
Yada Kanjanapan, Stephanie Lheureux, Amit M Oza
Introduction Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings in ovarian cancer. They inhibit single-stranded DNA repair, inducing synthetic lethality in cells with underlying homologous recombination deficiency (HRD). Marked responses are seen in ovarian cancers with breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutation, although up to 50% of high-grade serous ovarian cancers (HGSOC) have HRD may also benefit. Areas covered This review focuses on niraparib (oral PARP I and II inhibitor), its clinical testing in ovarian cancer, including the Myriad MyChoice HRD test as a potential companion diagnostic...
March 16, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28299675/a-regulatory-role-for-runx1-runx3-in-the-maintenance-of-genomic-integrity
#10
Vaidehi Krishnan, Yoshiaki Ito
All human cells are constantly attacked by endogenous and exogenous agents that damage the integrity of their genomes. Yet, the ensuing damage is mostly fixed and very rarely gives rise to genomic defects that promote cancer formation. This is due to the co-ordinated functioning of DNA repair proteins and checkpoint mechanisms that accurately detect and repair DNA damage to ensure genomic fitness. According to accumulating evidence, the RUNX family of transcription factors participate in the maintenance of genomic stability through transcriptional and non-transcriptional mechanisms...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28296948/determining-bacteriophage-endopeptidase-activity-using-either-fluorophore-quencher-labeled-peptides-combined-with-liquid-chromatography-mass-spectrometry-lc-ms-or-f%C3%A3-rster-resonance-energy-transfer-fret-assays
#11
Rolf Lood, Henrik Molina, Vincent A Fischetti
The necessity of identifying novel methods to combat infections caused by antibiotic resistant bacteria is increasing each year. Recent advancements in the development of peptidoglycan hydrolases (e.g. lysins) from bacterial viruses (bacteriophages) have revealed the efficiency of this class of enzymes in treating serious bacterial infections. Though promising results have been obtained regarding the lethal action of lysin on bacterial pathogens both in vitro and in vivo, an often-overlooked factor in these studies is precisely identifying their peptidoglycan cleavage site...
2017: PloS One
https://www.readbyqxmd.com/read/28296187/lethal-and-sublethal-effects-of-pesticides-in-the-management-of-polyphagotarsonemus-latus-banks-acari-tarsonemidae-on-capsicum-annuum-l
#12
Mariana O Breda, José V Oliveira, Alberto B Esteves Filho, Douglas R S Barbosa, Andrezo A Santos
BACKGROUND: The evaluation of lethal and sublethal effects are of great importance for a complete assessment of the total impact of chemical compounds upon pest populations and the development of management strategies. At this study, the lethal and sublethal effects of different synthetic and botanical products were evaluated upon the broad mite, Polyphagotarsonemus latus (Banks), a major pest of Capsicum annuum L and other crops. RESULTS: Abamectin presented the highest lethal effect to P...
March 15, 2017: Pest Management Science
https://www.readbyqxmd.com/read/28295846/the-enigmatic-oncogene-and-tumor-suppressor-like-properties-of-rad54b-insights-into-genome-instability-and-cancer
#13
REVIEW
Erin N McAndrew, Kirk J McManus
One of the major challenges to the cell is to ensure genome stability, which can be compromised through endogenous errors or exogenous DNA damaging agents, such as ionizing radiation or common chemotherapeutic agents. To maintain genome stability the cell has a multifaceted line of defense, including cell cycle checkpoints and DNA damage repair pathways. RAD54B is involved in many of these pathways and thus exhibits a role in maintaining and repairing genome stability following DNA damage. RAD54B is involved in cell cycle regulation after DNA damage and participates in homologous recombinational repair, which ensures the precise repair of the most deleterious DNA lesions, double-stranded breaks...
March 13, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28288817/animal-venoms-as-a-source-of-natural-antimicrobials-an-overview
#14
REVIEW
Ramar Perumal Samy, Bradley G Stiles, Octavio L Franco, Gautam Sethi, Lina Hk Lim
Hospitals are breeding grounds for many life-threatening bacteria worldwide. Clinically associated gram-positive bacteria such as Staphylococcus aureus/methicillin-resistant S. aureus and many others increase the risk of severe mortality and morbidity. The failure of antibiotics to kill various pathogens due to bacterial resistance highlights the urgent need to develop novel, potent, and less toxic agents from natural sources against various infectious agents. Currently, several promising classes of natural molecules from snake (terrestrial and sea), scorpion, spider, honey bee and wasp venoms hold promise as rich sources of chemotherapeutics against infectious pathogens...
March 10, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28287622/a-codon-shuffling-method-to-prevent-reversion-during-production-of-replication-defective-herpesvirus-stocks-implications-for-herpesvirus-vaccines
#15
Gang Li, Charles Ward, Rukhsana Yeasmin, Steven Skiena, Laurie T Krug, J Craig Forrest
Herpesviruses establish life-long chronic infections that place infected hosts at risk for severe disease. Herpesvirus genomes readily undergo homologous recombination (HR) during productive replication, often leading to wild-type (WT) reversion during complementation of replication-defective and attenuated viruses via HR with the helper gene provided in trans. To overcome this barrier, we developed a synthetic-biology approach based on a technique known as codon shuffling. Computer-assisted algorithms redistribute codons in a helper gene, thereby eliminating regions of homology, while enabling manipulation of factors such as codon-pair bias and CpG content to effectively titrate helper-gene protein levels...
March 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28286423/oligonucleotides-targeting-coagulation-factor-mrnas-use-in-thrombosis-and-hemophilia-research-and-therapy
#16
REVIEW
Marco Heestermans, Bart J M van Vlijmen
Small interfering (si) RNAs and antisense oligonucleotides (ASOs; here for simplicity reasons, both referred to as oligonucleotides) are small synthetic RNA or DNA molecules with a sequence complementary to a (pre)mRNA. Although the basic mechanisms of action between siRNAs and ASO are distinct, a sequence-specific interaction of the both oligonucleotides with the target (pre)mRNA alters the target's fate, which includes highly effective sequence-specific blockade of translation and consequently depletion of the corresponding protein...
2017: Thrombosis Journal
https://www.readbyqxmd.com/read/28286419/dual-roles-of-extracellular-signal-regulated-kinase-erk-in-quinoline-compound-bpiq-induced-apoptosis-and-anti-migration-of-human-non-small-cell-lung-cancer-cells
#17
Yao Fong, Chang-Yi Wu, Kuo-Feng Chang, Bing-Hung Chen, Wan-Ju Chou, Chih-Hua Tseng, Yen-Chun Chen, Hui-Min David Wang, Yeh-Long Chen, Chien-Chih Chiu
BACKGROUND: 2,9-Bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy] phenyl}-11H-indeno[1,2-c]quinoline-11-one (BPIQ), is a synthetic quinoline analog. A previous study showed the anti-cancer potential of BPIQ through modulating mitochondrial-mediated apoptosis. However, the effect of BPIQ on cell migration, an index of cancer metastasis, has not yet been examined. Furthermore, among signal pathways involved in stresses, the members of the mitogen-activated protein kinase (MAPK) family are crucial for regulating the survival and migration of cells...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28281199/unraveling-new-functions-of-superoxide-dismutase-using-yeast-model-system-beyond-its-conventional-role-in-superoxide-radical-scavenging
#18
REVIEW
Woo-Hyun Chung
To deal with chemically reactive oxygen molecules constantly threatening aerobic life, cells are readily equipped with elaborate biological antioxidant systems. Superoxide dismutase is a metalloenzyme catalytically eliminating superoxide radical as a first-line defense mechanism against oxidative stress. Multiple different SOD isoforms have been developed throughout evolution to play distinct roles in separate subcellular compartments. SOD is not essential for viability of most aerobic organisms and intriguingly found even in strictly anaerobic bacteria...
March 9, 2017: Journal of Microbiology / the Microbiological Society of Korea
https://www.readbyqxmd.com/read/28280262/marked-for-death-targeting-epigenetic-changes-in-cancer
#19
REVIEW
Sophia Xiao Pfister, Alan Ashworth
In the past few years, it has become clear that mutations in epigenetic regulatory genes are common in human cancers. Therapeutic strategies are now being developed to target cancers with mutations in these genes using specific chemical inhibitors. In addition, a complementary approach based on the concept of synthetic lethality, which allows exploitation of loss-of-function mutations in cancers that are not targetable by conventional methods, has gained traction. Both of these approaches are now being tested in several clinical trials...
March 10, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28270582/bacteria-getting-into-shape-genetic-determinants-of-e-%C3%A2-coli-morphology
#20
Shawn French, Jean-Philippe Côté, Jonathan M Stokes, Ray Truant, Eric D Brown
Perturbation of cellular processes is a prevailing approach to understanding biology. To better understand the complicated biology that defines bacterial shape, a sensitive, high-content platform was developed to detect multiple morphological defect phenotypes using microscopy. We examined morphological phenotypes across the Escherichia coli K-12 deletion (Keio) collection at the mid-exponential growth phase, revealing 111 deletions perturbing shape. Interestingly, 64% of these were uncharacterized mutants, illustrating the complex nature of shape maintenance and regulation in bacteria...
March 7, 2017: MBio
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