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Synthetic lethality

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https://www.readbyqxmd.com/read/29351298/construction-of-an-infectious-horsepox-virus-vaccine-from-chemically-synthesized-dna-fragments
#1
Ryan S Noyce, Seth Lederman, David H Evans
Edward Jenner and his contemporaries believed that his variolae vaccinae originated in horses and molecular analyses show that modern vaccinia virus (VACV) strains share common ancestry with horsepox virus (HPXV). Given concerns relating to the toxicity of modern VACV vaccines, we asked whether an HPXV-based vaccine might provide a superior alternative. Since HPXV may be extinct and the only specimen of HPXV that has been identified is unavailable for investigation, we explored whether HPXV could be obtained by large-scale gene synthesis...
2018: PloS One
https://www.readbyqxmd.com/read/29345572/breaking-the-dna-damage-response-via-serine-threonine-kinase-inhibitors-to-improve-cancer-treatment
#2
Wioletta Rozpedek, Dariusz Pytel, Alicja Nowak-Zdunczyk, Dawid Lewko, Radoslaw Wojtczak, John Alan Diehl, Ireneusz Majsterek
Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death...
January 16, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29343579/identification-of-poxvirus-genome-uncoating-and-dna-replication-factors-with-mutually-redundant-roles
#3
Baoming Liu, Debasis Panda, Jorge D Mendez-Rios, Sundar Ganesan, Linda S Wyatt, Bernard Moss
Genome uncoating is essential for replication of most viruses. For poxviruses, the process is divided into two stages: removal of the envelope allowing early gene expression, and breaching of the core wall allowing DNA release, replication and late gene expression. Subsequent studies showed that the host proteasome and the viral D5 protein, which has an essential role in DNA replication, are required for vaccinia virus (VACV) genome uncoating. In a search for additional VACV uncoating proteins, we noted a report that described a defect in DNA replication and late expression when the gene encoding a 68 kDa ankyrin-repeat/F box protein (68k-ank), associated with the cellular SCF ubiquitin ligase complex, was deleted from the attenuated modified vaccinia virus Ankara (MVA)...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29329694/management-of-refractory-vasodilatory-shock
#4
REVIEW
Jacob C Jentzer, Saraschandra Vallabhajosyula, Ashish K Khanna, Lakhmir S Chawla, Laurence W Busse, Kianoush B Kashani
Refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications. Approximately 7% of critically ill patients will develop refractory shock, with short-term mortality exceeding 50%. Refractory vasodilatory shock develops from uncontrolled vasodilation and vascular hyporesponsiveness to endogenous vasoconstrictors, causing failure of physiologic vasoregulatory mechanisms. Standard approaches to initial management of shock include fluid resuscitation and initiation of norepinephrine...
January 9, 2018: Chest
https://www.readbyqxmd.com/read/29329620/determination-and-validation-of-discriminating-concentration-of-ivermectin-against-rhipicephalus-microplus
#5
Abhijit Nandi, Sharath V Sagar, Gajanan Chigure, Ashutosh Fular, Anil Kumar Sharma, Gaurav Nagar, Sachin Kumar, B C Saravanan, Srikant Ghosh
Rhipicephalus microplus, the major cattle tick species of India is prevalent all over the country and causes huge economic loss directly or indirectly to the dairy industries. Chemical acaricides are playing an important role in managing tick infestations on livestock for many years and consequently, resistance to commonly used organophosphate (OP) and synthetic pyrethroid (SP) compounds has been reported. Subsequently, ivermectin (IVM) has been emerged as an alternative to manage OP and SP resistant ticks...
January 30, 2018: Veterinary Parasitology
https://www.readbyqxmd.com/read/29304403/targeting-death-receptors-for-drug-resistant-cancer-therapy-codelivery-of-ptrail-and-monensin-using-dual-targeting-and-stimuli-responsive-self-assembling-nanocomposites
#6
Fan Xu, Huihai Zhong, Ya Chang, Dongdong Li, Hongyue Jin, Meng Zhang, Huiyuan Wang, Chen Jiang, Youqing Shen, Yongzhuo Huang
Chemoresistance remains a formidable hurdle against cancer therapy. Seeking for novel therapy strategies is an urgent need for those who no longer benefit from chemotherapy. Chemoresistance is usually associated with the dysfunction of intrinsic apoptosis. Targeting extrinsic apoptosis via TRAIL signaling and the death receptors could be a potential solution to treat chemoresistant cancer. A highly biocompatible nano system for codelivery of the TRAIL DNA and the death receptor sensitizer monensin was developed, in which low-molecular-weight PEI (LMW-PEI) was crosslinked by the sulfhydryl cyclodextrin via disulfide bonds, and then bound with DNA, thus forming the bioreducible polyplex cores...
December 22, 2017: Biomaterials
https://www.readbyqxmd.com/read/29301272/skipping-multiple-exons-to-treat-dmd-promises-and-challenges
#7
REVIEW
Tejal Aslesh, Rika Maruyama, Toshifumi Yokota
Duchenne muscular dystrophy (DMD) is a lethal disorder caused by mutations in the DMD gene. Antisense-mediated exon-skipping is a promising therapeutic strategy that makes use of synthetic nucleic acids to skip frame-disrupting exon(s) and allows for short but functional protein expression by restoring the reading frame. In 2016, the U.S. Food and Drug Administration (FDA) approved eteplirsen, which skips DMD exon 51 and is applicable to approximately 13% of DMD patients. Multiple exon skipping, which is theoretically applicable to 80-90% of DMD patients in total, have been demonstrated in animal models, including dystrophic mice and dogs, using cocktail antisense oligonucleotides (AOs)...
January 2, 2018: Biomedicines
https://www.readbyqxmd.com/read/29300844/link-synthetic-lethality-to-drug-sensitivity-of-cancer-cells
#8
Ruiping Wang, Yue Han, Zhangxiang Zhao, Fan Yang, Tingting Chen, Wenbin Zhou, Xianlong Wang, Lishuang Qi, Wenyuan Zhao, Zheng Guo, Yunyan Gu
Synthetic lethal (SL) interactions occur when alterations in two genes lead to cell death but alteration in only one of them is not lethal. SL interactions provide a new strategy for molecular-targeted cancer therapy. Currently, there are few drugs targeting SL interactions that entered into clinical trials. Therefore, it is necessary to investigate the link between SL interactions and drug sensitivity of cancer cells systematically for drug development purpose. We identified SL interactions by integrating the high-throughput data from The Cancer Genome Atlas, small hairpin RNA data and genetic interactions of yeast...
December 28, 2017: Briefings in Bioinformatics
https://www.readbyqxmd.com/read/29300815/inhibited-trapped-or-adducted-the-optimal-selective-synthetic-lethal-mix-for-brcaness
#9
Andrew Tutt
No abstract text is available yet for this article.
December 28, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29300473/reconstitution-of-s-aureus-lipoteichoic-acid-synthase-activity-identifies-congo-red-as-a-selective-inhibitor
#10
Christopher Richard Vickery, B McKay Wood, Heidi Gabrielle Morris, Richard Losick, Suzanne Walker
Lipoteichoic acid (LTA) is an anionic surface polymer that is essential for normal growth of Staphylococcus aureus, making the LTA polymerase, LTA synthase (LtaS), a proposed drug target for combating Staphylococcal infections. LtaS is a poly-topic membrane protein with five membrane-spanning helices and an extracellular domain, and it uses phosphatidyl glycerol to assemble a glycerol phosphate chain on a glycosylated diacylglycerol membrane anchor. We report here the first reconstitution of LtaS polymerization activity and show that the azo dye Congo red inhibits this enzyme both in vitro and in cells...
January 4, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29299455/ezh2-dependent-therapies-in-bladder-cancer-synthetic-lethality
#11
EDITORIAL
Cristina Segovia, Jesús M Paramio
No abstract text is available yet for this article.
December 2017: Annals of Translational Medicine
https://www.readbyqxmd.com/read/29298360/chromosome-passenger-complex-is-required-for-the-survival-of-cells-with-ring-chromosomes-in-fission-yeast
#12
Ahmed G K Habib, Kanako Sugiura, Masaru Ueno
Ring chromosomes are circular chromosomal abnormalities that have been reported in association with some genetic disorders and cancers. In Schizosaccharomyces pombe, lack of function of protection of telomere 1 (Pot1) or telomerase catalytic subunit (Trt1) results in survivors with circular chromosomes. Hitherto, it is poorly understood how cells with circular chromosomes survive and how circular chromosomes are maintained. Fission yeast Cut17/Bir1, Ark1, Pic1, and Nbl1 is a conserved chromosome passenger complex (CPC) functioning mainly throughout mitosis...
2018: PloS One
https://www.readbyqxmd.com/read/29287114/postnatal-lethality-and-chondrodysplasia-in-mice-lacking-both-chondroitin-sulfate-n-acetylgalactosaminyltransferase-1-and-2
#13
Miki Shimbo, Riku Suzuki, Sayaka Fuseya, Takashi Sato, Katsue Kiyohara, Kozue Hagiwara, Risa Okada, Hiromasa Wakui, Yuki Tsunakawa, Hideto Watanabe, Koji Kimata, Hisashi Narimatsu, Takashi Kudo, Satoru Takahashi
Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) chain. In cartilage, CS plays important roles as the main component of the extracellular matrix (ECM), existing as side chains of the major cartilage proteoglycan, aggrecan. Six glycosyltransferases are known to coordinately synthesize the backbone structure of CS; however, their in vivo synthetic mechanism remains unknown. Previous studies have suggested that two glycosyltransferases, Csgalnact1 (t1) and Csgalnact2 (t2), are critical for initiation of CS synthesis in vitro...
2017: PloS One
https://www.readbyqxmd.com/read/29281970/transcriptional-effects-of-a-positive-feedback-circuit-in-drosophila-melanogaster
#14
Jarosław Bryk, R Guy Reeves, Floyd A Reed, Jai A Denton
BACKGROUND: Synthetic systems that use positive feedback have been developed to control human disease vectors and crop pests. The tTAV system, which has been deployed in several insect species, relies on a positive feedback circuit that can be inhibited via dietary tetracycline. Although insects carrying tTAV fail to survive until adulthood in the absence of tetracycline, the exact reason for its lethality, as well as the transcriptomic effects of an active positive feedback circuit, remain unknown...
December 28, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29281624/the-smc5-6-complex-regulates-the-yeast-mph1-helicase-at-rna-dna-hybrid-mediated-dna-damage
#15
Juan Lafuente-Barquero, Sarah Luke-Glaser, Marco Graf, Sonia Silva, Belén Gómez-González, Arianna Lockhart, Michael Lisby, Andrés Aguilera, Brian Luke
RNA-DNA hybrids are naturally occurring obstacles that must be overcome by the DNA replication machinery. In the absence of RNase H enzymes, RNA-DNA hybrids accumulate, resulting in replication stress, DNA damage and compromised genomic integrity. We demonstrate that Mph1, the yeast homolog of Fanconi anemia protein M (FANCM), is required for cell viability in the absence of RNase H enzymes. The integrity of the Mph1 helicase domain is crucial to prevent the accumulation of RNA-DNA hybrids and RNA-DNA hybrid-dependent DNA damage, as determined by Rad52 foci...
December 27, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29260919/the-development-of-parp-as-a-successful-target-for-cancer-therapy
#16
Roberto Ferrara, Francesca Simionato, Chiara Ciccarese, Elisabetta Grego, Sara Cingarlini, Roberto Iacovelli, Emilio Bria, Giampaolo Tortora, Davide Melisi
PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer...
December 20, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29259598/the-essential-upp-phosphatase-pair-bcrc-and-uppp-connects-cell-wall-homeostasis-during-growth-and-sporulation-with-cell-envelope-stress-response-in-bacillus-subtilis
#17
Jara Radeck, Nina Lautenschläger, Thorsten Mascher
The bacterial cell wall separates the cell from its surrounding and protects it from environmental stressors. Its integrity is maintained by a highly regulated process of cell wall biosynthesis. The membrane-located lipid II cycle provides cell wall building blocks that are assembled inside the cytoplasm to the outside for incorporation. Its carrier molecule, undecaprenyl phosphate (UP), is then recycled by dephosphorylation from undecaprenyl pyrophosphate (UPP). In Bacillus subtilis, this indispensable reaction is catalyzed by the UPP phosphatases BcrC and UppP...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29251726/orthologous-crispr-cas9-enzymes-for-combinatorial-genetic-screens
#18
Fadi J Najm, Christine Strand, Katherine F Donovan, Mudra Hegde, Kendall R Sanson, Emma W Vaimberg, Meagan E Sullender, Ella Hartenian, Zohra Kalani, Nicolo Fusi, Jennifer Listgarten, Scott T Younger, Bradley E Bernstein, David E Root, John G Doench
Combinatorial genetic screening using CRISPR-Cas9 is a useful approach to uncover redundant genes and to explore complex gene networks. However, current methods suffer from interference between the single-guide RNAs (sgRNAs) and from limited gene targeting activity. To increase the efficiency of combinatorial screening, we employ orthogonal Cas9 enzymes from Staphylococcus aureus and Streptococcus pyogenes. We used machine learning to establish S. aureus Cas9 sgRNA design rules and paired S. aureus Cas9 with S...
December 18, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/29245981/co-targeting-aurora-kinase-with-pd-l1-and-pi3k-abrogates-immune-checkpoint-mediated-proliferation-in-peripheral-t-cell-lymphoma-a-novel-therapeutic-strategy
#19
Shariful Islam, Eric Vick, Bryan Huber, Carla Morales, Catherine Spier, Laurence Cooke, Eric Weterings, Daruka Mahadevan
Peripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate ∼30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4+/CD8+ cells, we hypothesized that Program Death Ligand-1 (PD-L1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3Kα (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29237702/use-of-a-sibling-subtraction-method-ssm-for-identifying-causal-mutations-in-c-elegans-by-whole-genome-sequencing
#20
Braveen B Joseph, Nicolas A Blouin, David S Fay
Whole-genome sequencing (WGS) is an indispensible tool for identifying causal mutations obtained from genetic screens. To reduce the number of causal mutation candidates typically uncovered by WGS, C. elegans researchers have developed several strategies. One involves crossing N2-background mutants to the polymorphic HA strain, which can be used to simultaneously identify mutant-strain variants and obtain high-density mapping information. This approach, however, is not well suited for uncovering mutations in complex genetic backgrounds, and HA polymorphisms can alter phenotypes...
December 12, 2017: G3: Genes—Genomes—Genetics
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