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synthetic lethal

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Mutations in SF3B1 and SRSF2 common in myelodysplastic syndrome (MDS) are synthetic lethal.
August 17, 2018: Cancer Discovery
Yifan Liu, Eun Ju Yang, Baoyuan Zhang, Zhengqiang Miao, Changjie Wu, Junfang Lyu, Kaeling Tan, Terence Chuen Wai Poon, Joong Sup Shim
PTEN is a tumor suppressor found mutated in many cancers. From a synthetic lethality drug screen with PTEN-isogenic colorectal cancer cells, we found that mutant-PTEN cells were resistant to dual inhibitors of FLT3 and aurora kinase-A, including KW2449 and ENMD-2076. KW2449 significantly reduced the viability of wildtype-PTEN cells causing apoptosis, while little effect was observed in mutant-PTEN counterparts. Transcriptome profiling showed that members of PI3K-AKT signaling pathway were strongly changed in cells after KW2449 treatment, indicating a potential role of the pathway in drug resistance...
August 14, 2018: Cancer Letters
Edward A Motea, Farjana J Fattah, Ling Xiao, Luc Girard, Amy Rommel, Julio C Morales, Praveen Patidar, Yunyun Zhou, Andrew Porter, Yang Xie, John D Minna, David A Boothman
PURPOSE: Identification of novel strategies to expand the use of PARP inhibitors beyond BRCA deficiency is of great interest in personalized medicine. Here, we investigated the unannotated role of Kub5-HeraRPRD1B in homologous recombination (HR) repair and its potential clinical significance in targeted cancer therapy. EXPERIMENTAL DESIGN: Functional characterization of K-H alterations on HR repair of double-strand breaks (DSB) were assessed by targeted gene silencing, plasmid reporter assays, immunofluorescence and Western blots...
August 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hongwei Liao, Fang Ji, Thomas Helleday, Songmin Ying
Timely and faithful duplication of the entire genome depends on completion of replication. Replication forks frequently encounter obstacles that may cause genotoxic fork stalling. Nevertheless, failure to complete replication rarely occurs under normal conditions, which is attributed to an intricate network of proteins that serves to stabilize, repair and restart stalled forks. Indeed, many of the components in this network are encoded by tumour suppressor genes, and their loss of function by mutation or deletion generates genomic instability, a hallmark of cancer...
August 13, 2018: EMBO Reports
Stanley Chun-Wei Lee, Khrystyna North, Eunhee Kim, Eunjung Jang, Esther Obeng, Sydney X Lu, Bo Liu, Daichi Inoue, Akihide Yoshimi, Michelle Ki, Mirae Yeo, Xiao Jing Zhang, Min Kyung Kim, Hana Cho, Young Rock Chung, Justin Taylor, Benjamin H Durham, Young Joon Kim, Alessandro Pastore, Sebastien Monette, James Palacino, Michael Seiler, Silvia Buonamici, Peter G Smith, Benjamin L Ebert, Robert K Bradley, Omar Abdel-Wahab
Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence...
August 13, 2018: Cancer Cell
Goldie Y L Lui, Carla Grandori, Christopher J Kemp
Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterised CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock...
August 13, 2018: Journal of Clinical Pathology
Urvi A Shah, Elaine Y Chung, Orsolya Giricz, Kith Pradhan, Keisuke Kataoka, Shanisha Gordon-Mitchell, Tushar D Bhagat, Yun Mai, Yongqiang Wei, Elise Ishida, Gaurav S Choudhary, Ancy Joseph, Ronald Rice, Nadege Gitego, Crystall Parrish, Matthias Bartenstein, Swati Goel, Ioannis Mantzaris, Aditi Shastri, Olga Derman, Adam Binder, Kira Gritsman, Noah Kornblum, Ira Braunschweig, Chirag Bhagat, Jeff Hall, Armin Graber, Lee Ratner, Yanhua Wang, Seishi Ogawa, Amit Verma, B Hilda Ye, Murali Janakiram
Adult T cell leukemia lymphoma (ATLL) is a rare T cell neoplasm, endemic in the Japanese, Caribbean and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared to the Japanese ATLL. To determine genomic differences between these two cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results to the Japanese ATLL cases. Although the frequency of TP53 mutations was comparable, the mutation frequency in epigenetic and histone modifying genes (57%) was significantly higher whereas the mutation frequency in JAK/STAT and TCR/NF-κB pathway genes was significantly lower in our cohort...
August 13, 2018: Blood
Sung-Bau Lee, Sandra Segura-Bayona, Marina Villamor-Payà, Giulia Saredi, Matthew A M Todd, Camille Stephan-Otto Attolini, Ting-Yu Chang, Travis H Stracker, Anja Groth
DNA sequence and epigenetic information embedded in chromatin must be faithfully duplicated and transmitted to daughter cells during cell division. However, how chromatin assembly and DNA replication are integrated remains unclear. We examined the contribution of the Tousled-like kinases 1 and 2 (TLK1/TLK2) to chromatin assembly and maintenance of replication fork integrity. We show that TLK activity is required for DNA replication and replication-coupled nucleosome assembly and that lack of TLK activity leads to replication fork stalling and the accumulation of single-stranded DNA, a phenotype distinct from ASF1 depletion...
August 2018: Science Advances
Changjie Wu, Junfang Lyu, Eun Ju Yang, Yifan Liu, Baoyuan Zhang, Joong Sup Shim
ARID1A, a component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor with a high frequency of inactivating mutations in many cancers. Therefore, ARID1A deficiency has been exploited therapeutically for treating cancer. Here we show that ARID1A has a synthetic lethal interaction with aurora kinase A (AURKA) in colorectal cancer (CRC) cells. Pharmacological and genetic perturbations of AURKA selectively inhibit the growth of ARID1A-deficient CRC cells. Mechanistically, ARID1A occupies the AURKA gene promoter and negatively regulates its transcription...
August 10, 2018: Nature Communications
Lulu Liu, Shisheng Li, Sijing Wang, Ziyang Dong, Haichun Gao
Shewanella oneidensis is an extensively studied bacterium capable of respiring minerals as terminal electron acceptors (EAs), including a variety of iron ores. Although iron plays an essential and special role in iron respiration of S. oneidensis , little has been done to date to understand the characteristics of iron transport in this bacterium. In this study we report that all proteins encoded by the pub - putA - putB cluster for putrebactin ( S. oneidensis native siderophore) synthesis (PubABC), recognition-transport of Fe3+ -putrebactin across the outer-membrane (PutA), and reduction of ferric-putrebactin (PutB), are essential to the putrebactin-mediated iron uptake...
August 10, 2018: Applied and Environmental Microbiology
Dongsheng Duan
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin gene mutation. Conceptually, replacing the mutated gene with a normal one would cure the disease. However, this task has encountered significant challenges due to the enormous size of the gene and the distribution of muscle throughout the body. The former creates a hurdle for viral vector packaging and the latter begs for whole-body therapy. To address these obstacles, investigators have invented the highly abbreviated micro-dystrophin gene and developed body-wide systemic gene transfer with adeno-associated virus (AAV)...
July 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Aleksandar Vještica, Laura Merlini, Pedro Junior Nkosi, Sophie G Martin
The ploidy cycle, which is integral to sexual reproduction, requires meiosis to halve chromosome numbers as well as mechanisms that ensure zygotes are formed by exactly two partners1-4 . During sexual reproduction of the fungal model organism Schizosaccharomyces pombe, haploid P and M cells fuse to form a diploid zygote that immediately enters meiosis5 . Here we reveal that rapid post-fusion reconstitution of a bipartite transcription factor blocks re-fertilization. We first identify mutants that undergo transient cell fusion involving cytosol exchange but not karyogamy, and show that this drives distinct cell fates in the two gametes...
August 8, 2018: Nature
Jesse H Erasmus, Amit P Khandhar, Jeff Guderian, Brian Granger, Jacob Archer, Michelle Archer, Emily Gage, Jasmine Fuerte-Stone, Elise Larson, Susan Lin, Ryan Kramer, Rhea N Coler, Christopher B Fox, Dan T Stinchcomb, Steven G Reed, Neal Van Hoeven
Since the first demonstration of in vivo gene expression from an injected RNA molecule almost two decades ago,1 the field of RNA-based therapeutics is now taking significant strides, with many cancer and infectious disease targets entering clinical trials.2 Critical to this success has been advances in the knowledge and application of delivery formulations. Currently, various lipid nanoparticle (LNP) platforms are at the forefront,3 but the encapsulation approach underpinning LNP formulations offsets the synthetic and rapid-response nature of RNA vaccines...
August 2, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Luca Ronda, Barbara Pioselli, Silvia Catinella, Fabrizio Salomone, Marialaura Marchetti, Stefano Bettati
CHF5633 (Chiesi Farmaceutici, Italy) is a synthetic surfactant developed for respiratory distress syndrome replacement therapy in pre-term newborn infants. CHF5633 contains two phospholipids (dipalmitoylphosphatidylcholine and 1-palmitoyl-2oleoyl-sn-glycero-3-phosphoglycerol sodium salt), and peptide analogues of surfactant protein C (SP-C analogue) and surfactant protein B (SP-B analogue). Both proteins are fundamental for an optimal surfactant activity in vivo and SP-B genetic deficiency causes lethal respiratory failure after birth...
2018: PloS One
Mohammed Majrashi, Mohammed Almaghrabi, Maali Fadan, Ayaka Fujihashi, Brian Lee, Jack Deruiter, C Randall Clark, Muralikrishnan Dhanasekaran
Designer drugs are synthetically formulated to mimic the psychostimulatory effects of an original controlled/illegal drug of abuse. Designer drugs have similar chemical structure or functional analog as compared to existing controlled psychostimulatory drugs. There is a substantial rise in the production and use of designer drugs globally. Piperazine designer drugs were synthesized as an alternative to MDMA and have shown to induce numerous toxic effects leading to huge health, safety, law enforcement & monetary problems, and lethality...
July 29, 2018: Life Sciences
Masahiro Ito, Toshio Tanaka, Akinori Toita, Noriko Uchiyama, Hironori Kokubo, Nao Morishita, Michael G Klein, Hua Zou, Morio Murakami, Mitsuyo Kondo, Tomoya Sameshima, Shinsuke Araki, Satoshi Endo, Tomohiro Kawamoto, Gregg B Morin, Samuel A Aparicio, Atsushi Nakanishi, Hironobu Maezaki, Yasuhiro Imaeda
Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found in tumors and CDK12 inhibition sensitize cancer cells to DNA-damaging reagents and DNA-repair inhibitors. This suggests that CDK12 inhibitors are potential therapeutics for cancer that may cause synthetic lethality. Here, we report the discovery of 3-benzyl-1-(trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel and selective CDK12 inhibitors...
August 1, 2018: Journal of Medicinal Chemistry
Tanis D Godwin, S Thomas Kelly, Tom P Brew, Nicola M Bougen-Zhukov, Andrew B Single, Augustine Chen, Cassie E Stylianou, Lawrence D Harris, Sophie K Currie, Bryony J Telford, Henry G Beetham, Gary B Evans, Michael A Black, Parry J Guilford
BACKGROUND: The E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers. METHODS: Density distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1-/- cells were used to identify protein classes affected by CDH1 mutation...
July 31, 2018: Gastric Cancer
Sarah Elliott, Amelia A Keaton, Jacqueline D Chu, Charles C Reed, Bradley Garman, Ami Patel, Jian Yan, Kate E Broderick, David Weiner
Influenza-A H3N2 viruses circulate globally, leading to substantial morbidity and mortality. Commercially-available, antigen-matched influenza vaccines must be updated frequently to match dynamic sequence variability in immune epitopes, especially within viral hemagglutinin H3. In an effort to create comprehensive immune responses against H3N2, we developed four micro-consensus antigens designed to mimic the sequence and antigenic diversity of H3. Synthetic plasmid DNA constructs were constructed to express each micro-consensus immunogen, and combined into a multi-antigen DNA vaccine cocktail, pH3HA...
July 31, 2018: Human Gene Therapy
Shaoli Das, Xiang Deng, Kevin Camphausen, Uma Shankavaram
Summary: Synthetic lethality is a state when simultaneous loss of two genes is lethal to a cancer cell, while the loss of the individual genes is not. We developed an R package DiscoverSL to predict and visualize synthetic lethality in cancers using multi-omic cancer data. Mutation, copy number alteration, and gene expression data from The Cancer Genome Atlas (TCGA) project were combined to develop a multi-parametric Random Forest classifier. The effects of selectively targeting the predicted synthetic lethal genes is tested in silico using shRNA and drug screening data from cancer cell line databases...
July 28, 2018: Bioinformatics
Tao Li, Hongyun Wang, Xiubo Xia, Shoujun Cao, Jiangang Yao, Lili Zhang
Root-knot nematodes (RKNs; Meloidogyne spp.) are obligate endoparasites that infect many crops and cause severe yield losses. In this research, we studied the effect of Welsh onion, grown as a companion plant, on the resistance of cucumber plants to RKN infection and analyzed the most abundant components of Welsh onion root exudates. The results showed that, when grown with Welsh onion as a companion plant, cucumber roots had 77.0% fewer root knots and egg masses than the control cucumber roots. Welsh onion root exudates were collected and extracted with chloroform, ethyl ether, n-butanol and ethyl acetate...
2018: PloS One
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