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Synthetic lethality

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https://www.readbyqxmd.com/read/28092680/utilizing-somatic-mutation-data-from-numerous-studies-for-cancer-research-proof-of-concept-and-applications
#1
D Amar, S Izraeli, R Shamir
Large cancer projects measure somatic mutations in thousands of samples, gradually assembling a catalog of recurring mutations in cancer. Many methods analyze these data jointly with auxiliary information with the aim of identifying subtype-specific results. Here, we show that somatic gene mutations alone can reliably and specifically predict cancer subtypes. Interpretation of the classifiers provides useful insights for several biomedical applications. We analyze the COSMIC database, which collects somatic mutations from The Cancer Genome Atlas (TCGA) as well as from many smaller scale studies...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28092425/chemical-composition-of-the-essential-oil-of-nigeria-grown-hoslundia-opposita-vahl-lamiaceae-dried-leaves-and-its-bioactivity-against-cowpea-seed-bruchid
#2
Samuel Adelani Babarinde, Olufemi Olutoyin Richard Pitan, Ganiyu Olatunji Olatunde, Michael Oluwole Ajala
Due to several ecological and human hazards of synthetic pesticides in postharvest crop protection, there is the need to search for eco-friendly alternatives. In this study, chemical composition and insecticidal activities of essential oil (EO) obtained from Hoslundia opposita dried leaves were evaluated against cowpea seed bruchid. Eight constituents, predominated by oxygenated monoterpenes (78.86%), were identified using GC-MS. The constituents were 1,8-cineole (1; 61.15%), followed by α-terpineol (2; 16...
January 16, 2017: Chemistry & Biodiversity
https://www.readbyqxmd.com/read/28089747/metabolic-engineering-of-a-diazotrophic-bacterium-improves-ammonium-release-and-biofertilization-of-plants-and-microalgae
#3
Rafael Ambrosio, Juan Cesar Federico Ortiz-Marquez, Leonardo Curatti
The biological nitrogen fixation carried out by some Bacteria and Archaea is one of the most attractive alternatives to synthetic nitrogen fertilizers. However, with the exception of the symbiotic rhizobia-legumes system, progress towards a more extensive realization of this goal has been slow. In this study we manipulated the endogenous regulation of both nitrogen fixation and assimilation in the aerobic bacterium Azotobacter vinelandii. Substituting an exogenously inducible promoter for the native promoter of glutamine synthetase produced conditional lethal mutant strains unable to grow diazotrophically in the absence of the inducer...
January 9, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28087713/functional-genomics-reveals-that-tumors-with-activating-phosphoinositide-3-kinase-mutations-are-dependent-on-accelerated-protein-turnover
#4
Teresa Davoli, Kristen E Mengwasser, Jingjing Duan, Ting Chen, Camilla Christensen, Eric C Wooten, Anthony N Anselmo, Mamie Z Li, Kwok-Kin Wong, Kristopher T Kahle, Stephen J Elledge
Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28087320/poly-adp-ribose-polymerase-activity-and-inhibition-in-cancer
#5
REVIEW
Caleb Dulaney, Samuel Marcrom, Jennifer Stanley, Eddy S Yang
Genomic instability resultant from defective DNA repair mechanisms is a fundamental hallmark of cancer. The poly(ADP-ribose) polymerase (PARP) proteins 1, 2 and 3 catalyze the polymerization of poly(ADP-ribose) and covalent attachment to proteins in a phylogenetically ancient form of protein modification. PARPs play a role in base excision repair, homologous recombination, and non-homologous end joining. The discovery that loss of PARP activity had cytotoxic effects in cells deficient in homologous recombination has sparked a decade of translational research efforts that culminated in the FDA approval of an oral PARP inhibitor for clinical use in patients with ovarian cancer and defective homologous recombination...
January 10, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/28069876/targeting-plk1-to-enhance-efficacy-of-olaparib-in-castration-resistant-prostate-cancer
#6
Xiaoqi Liu, Jie Li, Ruixin Wang, Yifan Kong, Meaghan M Broman, Colin Carlock, Long Chen, Zhiguo Li, Elia Farah, Timothy L Ratliff
Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors...
January 9, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28069724/synthetic-lethality-exploitation-by-an-anti-trop-2-sn-38-antibody-drug-conjugate-immu-132-plus-parp-inhibitors-in-brca1-2-wild-type-triple-negative-breast-cancer
#7
Thomas M Cardillo, Robert M Sharkey, Diane L Rossi, Roberto Arrojo, Ali Mostafa, David M Goldenberg
PURPOSE: Both Poly(ADP-ribose) polymerase inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC. EXPERIMENTAL DESIGN: In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, double-stranded DNA (dsDNA) breaks, and cell-cycle arrest...
January 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28055979/-back-to-a-false-normality-new-intriguing-mechanisms-of-resistance-to-parp-inhibitors
#8
REVIEW
Lorena Incorvaia, Francesc Passiglia, Sergio Rizzo, Antonio Galvano, Angela Listì, Nadia Barraco, Rossella Maragliano, Valentina Calò, Clara Natoli, Marcello Ciaccio, Viviana Bazan, Antonio Russo
Several evidences have shown that BRCA mutations increased tumor-cells sensitivity to PARP inhibitors by synthetic lethality leading to an accelerated development of several compounds targeting the PARP enzymes system as anticancer agents for clinical setting. Most of such compounds have been investigated in ovarian and breast cancer, showing promising efficacy in BRCA-mutated patients. Recently clinical studies of PARP-inhibitors have been extended across different tumor types harboring BRCA-mutations, including also "BRCA-like" sporadic tumors with homologous recombination deficiency (HRD)...
December 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/28043394/first-documentation-of-ivermectin-resistance-in-rhipicephalus-sanguineus-sensu-lato-acari-ixodidae
#9
R I Rodriguez-Vivas, M M Ojeda-Chi, I Trinidad-Martinez, A A Pérez de León
: The brown dog tick, Rhipicephalus sanguineus sensu lato (Latreille, 1806), is an ectoparasite and disease vector of significant veterinary and public health importance that is distributed widely around the world. The intensive use of synthetic acaricides for tick control exerts a strong selective pressure for brown dog ticks to become resistant to them. Here, we investigated claims from the field regarding treatment failure associated with the use of veterinary products containing ivermectin (IVM) to control brown dog ticks infesting dogs in Yucatan state, Mexico...
January 15, 2017: Veterinary Parasitology
https://www.readbyqxmd.com/read/28043384/initial-evaluations-of-the-effectiveness-of-spinetoram-as-a-long-acting-oral-systemic-pulicide-for-controlling-cat-flea-ctenocephalides-felis-infestations-on-dogs
#10
W Hunter White, Kari L Riggs, Michelle L Totten, Daniel E Snyder, Christine M McCoy, David R Young
Spinetoram is a semi-synthetic, spinosyn class natural product derived from fermentation by the actinomycete, Saccharopolyspora spinosa. Based on LD50 (50% lethal dose) values against adult cat fleas (Ctenocephalides felis) using an in vitro contact assay, spinetoram was approximately 4-fold more potent than spinosad. Subsequently, two parallel-arm, randomized block design laboratory studies were conducted to evaluate the effectiveness of orally administered spinetoram against experimental C. felis infestations on dogs, when administered as a single dose or multiple doses over a 6-12h interval...
January 15, 2017: Veterinary Parasitology
https://www.readbyqxmd.com/read/28028542/syrosingopine-sensitizes-cancer-cells-to-killing-by-metformin
#11
Don Benjamin, Marco Colombi, Sravanth K Hindupur, Charles Betz, Heidi A Lane, Mahmoud Y M El-Shemerly, Min Lu, Luca Quagliata, Luigi Terracciano, Suzette Moes, Timothy Sharpe, Aleksandra Wodnar-Filipowicz, Christoph Moroni, Michael N Hall
We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine's known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound...
December 2016: Science Advances
https://www.readbyqxmd.com/read/28025559/cancer-s-achilles-heel-apoptosis-and-necroptosis-to-the-rescue
#12
REVIEW
Atreyi Dasgupta, Motonari Nomura, Ryan Shuck, Jason Yustein
Apoptosis, and the more recently discovered necroptosis, are two avenues of programmed cell death. Cancer cells survive by evading these two programs, driven by oncogenes and tumor suppressor genes. While traditional therapy using small molecular inhibitors and chemotherapy are continuously being utilized, a new and exciting approach is actively underway by identifying and using synergistic relationship between driver and rescue genes in a cancer cell. Through these synthetic lethal relationships, we are gaining tremendous insights into tumor vulnerabilities and specific molecular avenues for induction of programmed cell death...
December 23, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28025497/mechanisms-governing-ddk-regulation-of-the-initiation-of-dna-replication
#13
REVIEW
Larasati, Bernard P Duncker
The budding yeast Dbf4-dependent kinase (DDK) complex-comprised of cell division cycle (Cdc7) kinase and its regulatory subunit dumbbell former 4 (Dbf4)-is required to trigger the initiation of DNA replication through the phosphorylation of multiple minichromosome maintenance complex subunits 2-7 (Mcm2-7). DDK is also a target of the radiation sensitive 53 (Rad53) checkpoint kinase in response to replication stress. Numerous investigations have determined mechanistic details, including the regions of Mcm2, Mcm4, and Mcm6 phosphorylated by DDK, and a number of DDK docking sites...
December 22, 2016: Genes
https://www.readbyqxmd.com/read/28024216/toxicity-accumulation-and-trophic-transfer-of-chemically-and-biologically-synthesized-nano-zero-valent-iron-in-a-two-species-freshwater-food-chain
#14
M Bhuvaneshwari, Deepak Kumar, Rajdeep Roy, Susiddharthak Chakraborty, Abhinav Parashar, Anita Mukherjee, N Chandrasekaran, Amitava Mukherjee
The impact of bio-remediation agent nZVI on environment is still inadequately understood, especially on aquatic food web. The study presented here has therefore considered both chemical (CS) and biological (BS) synthetic origins of nZVI and their effects on both algae and daphnia. The study is unique in its attempt to explore the possibility of trophic transfer from algae to its immediate higher niche (daphnia as the model). An equal weightage of the effects of both CS and BS nZVI on algae and daphnia has been explored here; hence it allows us to compare the capping of nZVI on toxicity...
December 21, 2016: Aquatic Toxicology
https://www.readbyqxmd.com/read/28017138/sumoylation-pathway-as-potential-therapeutic-targets-in-cancer
#15
L Gong, R Qi, D W-C Li
Sumoylation is a covalent protein posttranslational modification that conjugates the small ubiquitin-like peptide SUMO to substrate. Sumoylation is critically implicated in multiple biological processes, including cell proliferation, differentiation, senescence and apoptosis, etc. Therefore, it is not surprising that dysregulation of sumoylation has been implicated in tumorigenesis and different types of cancer were found to be addicted to functional sumoylation pathway. The potential role for sumoylation as a therapeutic target in caner is emerging...
December 22, 2016: Current Molecular Medicine
https://www.readbyqxmd.com/read/28010038/suppression-and-synthetic-lethal-genetic-relationships-of-%C3%AE-gpsb-mutations-indicate-that-gpsb-mediates-protein-phosphorylation-and-penicillin-binding-protein-interactions-in-streptococcus-pneumoniae-d39
#16
Britta E Rued, Jiaqi J Zheng, Andrea Mura, Ho-Ching T Tsui, Michael J Boersma, Jeffrey L Mazny, Federico Corona, Amilcar J Perez, Daniela Fadda, Linda Doubravová, Karolína Buriánková, Pavel Branny, Orietta Massidda, Malcolm E Winkler
GpsB regulatory protein and StkP protein kinase have been proposed as molecular switches that balance septal and peripheral (side-wall like) peptidoglycan (PG) synthesis in Streptococcus pneumoniae (pneumococcus); yet, mechanisms of this switching remain unknown. We report that ΔdivIVA mutations are not epistatic to ΔgpsB division-protein mutations in progenitor D39 and related genetic backgrounds; nor is GpsB required for StkP localization or FDAA labeling at septal division rings. However, we confirm that reduction of GpsB amount leads to decreased protein phosphorylation by StkP and report that the essentiality of ΔgpsB mutations is suppressed by inactivation of PhpP protein phosphatase, which concomitantly restores protein phosphorylation levels...
December 23, 2016: Molecular Microbiology
https://www.readbyqxmd.com/read/28009306/cancer-specific-synthetic-lethality-between-atr-and-chk1-kinase-activities
#17
Kumar Sanjiv, Anna Hagenkort, José Manuel Calderón-Montaño, Tobias Koolmeister, Philip M Reaper, Oliver Mortusewicz, Sylvain A Jacques, Raoul V Kuiper, Niklas Schultz, Martin Scobie, Peter A Charlton, John R Pollard, Ulrika Warpman Berglund, Mikael Altun, Thomas Helleday
No abstract text is available yet for this article.
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/28009252/structural-basis-for-the-inhibition-of-recbcd-by-gam-and-its-synergistic-antibacterial-effect-with-quinolones
#18
Martin Wilkinson, Lucy Troman, Wan Ak Wan Nur Ismah, Yuriy Chaban, Matthew B Avison, Mark S Dillingham, Dale B Wigley
Our previous paper (Wilkinson et al, 2016) used high-resolution cryo-electron microscopy to solve the structure of the Escherichia coli RecBCD complex, which acts in both the repair of double-stranded DNA breaks and the degradation of bacteriophage DNA. To counteract the latter activity, bacteriophage λ encodes a small protein inhibitor called Gam that binds to RecBCD and inactivates the complex. Here, we show that Gam inhibits RecBCD by competing at the DNA-binding site. The interaction surface is extensive and involves molecular mimicry of the DNA substrate...
December 23, 2016: ELife
https://www.readbyqxmd.com/read/28003236/targeting-dna-repair-in-cancer-beyond-parp-inhibitors
#19
REVIEW
Jessica S Brown, Brent O'Carrigan, Stephen P Jackson, Timothy A Yap
: Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair...
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28002024/the-cancer-cell-adhesion-resistome-mechanisms-targeting-and-translational-approaches
#20
Ellen Dickreuter, Nils Cordes
Cell adhesion-mediated resistance limits the success of cancer therapies and is a great obstacle to overcome in the clinic. Since the 90s, where it became clear that adhesion of tumor cells to the extracellular matrix is an important mediator of therapy resistance, a lot of work has been conducted to understand the fundamental underlying mechanisms and two paradigms were deduced: cell adhesion-mediated radioresistance (CAM-RR) and cell adhesion-mediated drug resistance (CAM-DR). Preclinical work has evidently demonstrated that targeting of integrins, adapter proteins and associated kinases comprising the cell adhesion resistome is a promising strategy to sensitize cancer cells to both radiotherapy and chemotherapy...
December 20, 2016: Biological Chemistry
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