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synthetic lethal

Catalina Rey-Valeirón, Keila Pérez, Lucía Guzmán, Javier López-Vargas, Eduardo Valarezo
The current concern about resistance to acaricides and the impact of toxic waste on the environment has led to the search of vegetal alternatives in the control of the brown tick of the dog Rhipicephalus sanguineus. Schinus molle L. (Anacardiaceae) derivatives have been associated with insecticidal, antimicrobial and antiprotozoal activities and essential oil showed to be lethal to R. microplus larvae. This study aimed at evaluating the acaricidal effect of essential oil of S. molle (EOSm ) on engorged adult females and larval stages of R...
October 13, 2018: Experimental & Applied Acarology
Yuan Tian, Mo-Xian Chen, Jing-Fang Yang, H H K Achala, Bei Gao, Ge-Fei Hao, Guang-Fu Yang, Zhi-Yong Dian, Qi-Juan Hu, Di Zhang, Jianhua Zhang, Ying-Gao Liu
This study systematically identifies plant SYF2/NTC31/p29 genes from 62 plant species by a combinatory bioinformatics approach, revealing the importance of this gene family in phylogenetics, duplication, transcriptional, and post-transcriptional regulation. Alternative splicing is a post-transcriptional regulatory mechanism, which is critical for plant development and stress responses. The entire process is strictly attenuated by a complex of splicing-related proteins, designated splicing factors. Human p29, also referred to as synthetic lethal with cdc forty 2 (SYF2) or the NineTeen complex 31 (NTC31), is a core protein found in the NTC complex of humans and yeast...
October 13, 2018: Planta
Sarah Croessmann, Luigi Formisano, Lisa Kinch, Paula I Gonzalez-Ericsson, Dhivya R Sudhan, Rebecca J Nagy, Aju Mathew, Eric H Bernicker, Massimo Cristofanilli, Jie He, Richard E Cutler, Alshad S Lalani, Vincent A Miller, Richard B Lanman, Nick Grishin, Carlos L Arteaga
PURPOSE: We examined the role of ERBB2 activating mutations in endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer. Design ERBB2 mutation frequency was determined from large genomic databases. Isogenic knock-in ERBB2 mutations in ER+ MCF7 cells and xenografts were used to investigate estrogen-independent growth. Structural analysis was used to determine the molecular interaction of HER L755S with HER3. Small molecules and siRNAs were used to inhibit PI3Kα, TORC1 and HER3...
October 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ami Patel, Emma L Reuschel, Kimberly A Kraynyak, Trina Racine, Daniel H Park, Veronica L Scott, Jonathan Audet, Dinah Amante, Megan C Wise, Amelia A Keaton, Gary Wong, Daniel O Villarreal, Jewell Walters, Kar Muthumani, Devon J Shedlock, Marc-Antoine de La Vega, Ross Plyler, Jean Boyer, Kate E Broderick, Jian Yan, Amir S Khan, Shane Jones, Alexander Bello, Geoff Soule, Kaylie N Tran, Shihua He, Kevin Tierney, Xiangguo Qiu, Gary P Kobinger, Niranjan Y Sardesai, David B Weiner
Background: There remains an important need for prophylactic anti-Ebola virus vaccine candidates that elicit long-lasting immune responses and can be delivered to vulnerable populations that are unable to receive live-attenuated or viral vector vaccines. Methods: We designed novel synthetic anti-Ebola virus glycoprotein (EBOV-GP) DNA vaccines as a strategy to expand protective breadth against diverse EBOV strains and evaluated the impact of vaccine dosing and route of administration on protection against lethal EBOV-Makona challenge in cynomolgus macaques...
October 10, 2018: Journal of Infectious Diseases
Shuai Wu, Nail Fatkhutdinov, Takeshi Fukumoto, Benjamin G Bitler, Pyoung Hwa Park, Andrew V Kossenkov, Marco Trizzino, Hsin-Yao Tang, Lin Zhang, Alessandro Gardini, David W Speicher, Rugang Zhang
Inactivation of the subunits of SWI/SNF complex such as ARID1A is synthetically lethal with inhibition of EZH2 activity. However, mechanisms of de novo resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated cells. SMARCA4 loss upregulates anti-apoptotic genes in the EZH2 inhibitor-resistant cells. EZH2 inhibitor-resistant ARID1A-mutated cells are hypersensitive to BCL2 inhibitors such as ABT263...
October 8, 2018: Nature Communications
Reem Ali, Abdulbaqi Al-Kawaz, Michael S Toss, Andrew R Green, Islam M Miligy, Katia A Mesquita, Claire Seedhouse, Sameer Mirza, Vimla Band, Emad A Rakha, Srinivasan Madhusudan
Targeting PARP1 for synthetic lethality is a new strategy for breast cancers harboring germline mutations in BRCA. However, these mutations are rare, and reactivation of BRCA-mediated pathways may result in eventual resistance to PARP1 inhibitor therapy. Alternative synthetic lethality approaches targeting more common sporadic breast cancers and pre-invasive ductal carcinoma in situ (DCIS) are desirable. Here we show that downregulation of XRCC1, which interacts with PARP1 and coordinates base excision repair, is an early event in human breast cancer pathogenesis...
October 8, 2018: Cancer Research
Ryan P Barnes, Wei-Chung Tsao, George-Lucian Moldovan, Kristin A Eckert
Neoplastic transformation and genome instability are enhanced by replication stress, conditions that slow or stall DNA replication forks. Consequently, cancer cells require multiple enzymes and checkpoint signaling pathways to mitigate replication stress for their viability and proliferation. Targeting proteins that enhance cancer cell survival during replication stress is a recent approach in clinical strategies, especially when targets produce synthetic lethality. DNA polymerase eta (Pol η) has many key functions in genome stability, particularly for translesion synthesis...
October 8, 2018: Cancer Research
Pedro Isaacsson Velho, Fahad Qazi, Sayeedul Hassan, Michael A Carducci, Samuel R Denmeade, Mark C Markowski, Daniel L Thorek, Theodore L DeWeese, Daniel Y Song, Phuoc T Tran, Mario A Eisenberger, Emmanuel S Antonarakis
BACKGROUND: Pathogenic mutations in genes mediating homologous recombination (HR) DNA repair are present in 20-30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment. OBJECTIVE: To evaluate the potential impact of germline or somatic HR-deficiency (HRD) mutations on radium-223 efficacy in mCRPC with bone metastasis...
October 4, 2018: European Urology
Zhendong Yang, Kathy S Xue, Xiulan Sun, Phillip L Williams, Jia-Sheng Wang, Lili Tang
In this study, the possible molecular mechanisms of zearalenone (ZEA)-induced reproductive and developmental toxic effects in Caenorhabditis elegans (C. elegans) were investigated. Differential gene expression profiles were identified, and 171, 245, and 3149 genes were down- or up-regulated (>2.0 fold) in 10, 20, and 40 μg/ml ZEA treated groups, respectively, as compared to untreated controls. Pathway specific mapping showed that the major differentially expressed genes were collagen synthetic pathways regulating genes, col-121 and dpy-17...
October 4, 2018: Food and Chemical Toxicology
Colm J Ryan, Ilirjana Bajrami, Christopher J Lord
Synthetic lethality has long been proposed as an approach for targeting genetic defects in tumours. Despite a decade of screening efforts, relatively few robust synthetic lethal targets have been identified. Improved genetic perturbation techniques, including CRISPR/Cas9 gene editing, have resulted in renewed enthusiasm for searching for synthetic lethal effects in cancer. An implicit assumption behind this enthusiasm is that the lack of reproducibly identified targets can be attributed to limitations of RNAi technologies...
October 2018: Trends in Cancer
Tor-Christian Aase Johannessen, Md Abdul Mahdi Hasan-Olive, Huaiyang Zhu, Oxana Denisova, Amra Grudic, Md Latif, Halala Saed, Jobin K Varughese, Gro Vatne Røsland, Ning Yang, Terje Sundstrøm, Anne Nordal, Karl Johan Tronstad, Jian Wang, Morten Lund-Johansen, Anne Simonsen, Bassam Janji, Jukka Westermarck, Rolf Bjerkvig, Lars Prestegarden
Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14-15 months following surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome-wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression...
October 5, 2018: International Journal of Cancer. Journal International du Cancer
Chiaki Fujiwara, Yukiko Muramatsu, Megumi Nishii, Kazuhiro Tokunaka, Hidetoshi Tahara, Masaru Ueno, Takao Yamori, Yoshikazu Sugimoto, Hiroyuki Seimiya
Telomere maintenance by telomerase activity supports the infinite growth of cancer cells. MST-312, a synthetic telomerase inhibitor, gradually shortens telomeres at non-acute lethal doses and eventually induces senescence and apoptosis of telomerase-positive cancer cells. Here we report that MST-312 at higher doses works as a dual inhibitor of telomerase and DNA topoisomerase II and exhibits acute anti-proliferative effects on cancer cells and xenografted tumours in vivo. Our cell-based chemical fingerprinting approach revealed that cancer cells with shorter telomeres and lower expression of lamin A, a nuclear architectural protein, exhibited higher sensitivity to the acute deleterious effects of MST-312, accompanied by formation of telomere dysfunction-induced foci and DNA double-strand breaks...
October 4, 2018: Scientific Reports
Adnan Ahmad Ansari, Inkeun Park, Inki Kim, Sojung Park, Sung-Min Ahn, Jae-Lyun Lee
BACKGROUND: Bladder cancer has numerous genomic features that are potentially actionable by targeted agents. Nevertheless, both pre-clinical and clinical research using molecular targeted agents have been very limited in bladder cancer. RESULTS: We created the Genomics of Drug Sensitivity in Bladder Cancer (GDBC) database, an integrated database (DB) to facilitate the genomic understanding of bladder cancer in relation to drug sensitivity, in order to promote potential therapeutic applications of targeted agents in bladder cancer treatment...
October 3, 2018: BMC Medical Genomics
Carlos Santolaria, Diego Velázquez, Erick Strauss, Joaquín Ariño
S. cerevisiae Hal3 (ScHal3) is a moonlighting protein that, is in its monomeric state, regulates the Ser/Thr protein phosphatase Ppz1, but also joins ScCab3 (and in some instances the Hal3 paralog Vhs3) to form an unusual heterotrimeric phosphopantothenoylcysteine decarboxylase (PPCDC) enzyme. PPCDC is required for CoA biosynthesis and in most eukaryotes is a homotrimeric complex with three identical catalytic sites at the trimer interfaces. However, in S. cerevisiae the heterotrimeric arrangement results in a single functional catalytic center...
October 2, 2018: Scientific Reports
Margaret Nieborowska-Skorska, Silvia Maifrede, Min Ye, Monika Toma, Elizabeth Hewlett, John Gordon, Bac Viet Le, Tomasz Sliwinski, Huaqing Zhao, Katarzyna Piwocka, Peter Valent, Alexei V Tulin, Wayne Childers, Tomasz Skorski
No abstract text is available yet for this article.
October 2, 2018: Leukemia & Lymphoma
Binod Prasad, Wolfgang Lein, General Thiyam, Christoph Peter Lindenberger, Rainer Buchholz, Nithya Vadakedath
A mutated phytoene desaturase (pds) gene, pds-L504R, conferring resistance to the herbicide norflurazon has been reported as a dominant selectable marker for the genetic engineering of microalgae (Steinbrenner and Sandmann in Appl Environ Microbiol 72:7477-7484, 2006; Prasad et al. in Appl Microbiol Biotechnol 98(20):8629-8639, 2014). However, this mutated genomic clone harbors several introns and the entire expression cassette including its native promoter and terminator has a length > 5.6 kb, making it unsuitable as a standard selection marker...
October 1, 2018: Photosynthesis Research
Meagan B Ryan, Ryan B Corcoran
RAS genes are the most commonly mutated oncogenes in cancer, but effective therapeutic strategies to target RAS-mutant cancers have proved elusive. A key aspect of this challenge is the fact that direct inhibition of RAS proteins has proved difficult, leading researchers to test numerous alternative strategies aimed at exploiting RAS-related vulnerabilities or targeting RAS effectors. In the past few years, we have witnessed renewed efforts to target RAS directly, with several promising strategies being tested in clinical trials at different stages of completion...
October 1, 2018: Nature Reviews. Clinical Oncology
Chen-Fei Low, Mohd Radzi Md Yusoff, Giva Kuppusamy, Nur Farahiyah Ahmad Nadzri
Macrobrachium rosenbergii nodavirus (MrNV) has been threatening the giant freshwater prawn aquaculture since 1997, causing white tail disease in the prawn species that leads to 100% lethality of the infected postlarvae. Comprehension of the viral infectivity and pathogenesis at molecular biology level has recently resolved the viral capsid protein and evidenced the significant difference in the viral structural protein compared to other nodaviruses that infect fish and insect. Cumulative researches have remarked the proposal to assert MrNV as a member of new genus, gammanodavirus to the Nodaviridae family...
October 1, 2018: Journal of Fish Diseases
Hui-Ju Jang, Yesol Bak, Thu-Huyen Pham, Sae-Bom Kwon, Bo-Yeon Kim, JinTae Hong, Do-Young Yoon
Colon cancer is one of the most lethal and common malignancies worldwide. STK899704, a novel synthetic agent, has been reported to exhibit anticancer effects towards numerous cancer cells. However, the effect of STK899704 on the biological properties of colon cancer, including cancer cell migration and cancer stem cells (CSCs), remains unknown. Here, we examined the inhibitory effect of STK899704 on cell migration and CSC stemness. In the wound healing assay, STK899704 significantly inhibited the motility of colon cancer cells...
October 1, 2018: BMB Reports
Brittany Haynes, Junko Murai, Jung-Min Lee
Poly(ADP-ribose) polymerase (PARP) inhibition serves as a potent therapeutic option eliciting synthetic lethality in cancers harboring homologous recombination (HR) repair defects, such as BRCA mutations. However, the development of resistance to PARP inhibitors (PARPis) poses a clinical challenge. Restoration of HR competency is one of the many molecular factors contributing to PARPi resistance. Combination therapy with cell cycle checkpoint (ATR, CHK1, and WEE1) inhibitors is being investigated clinically in many cancers, particularly in ovarian cancer, to enhance the efficacy and circumvent resistance to PARPis...
September 11, 2018: Cancer Treatment Reviews
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